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BackgroundPrevious analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.Patients and methodsThis double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.ResultsBetween 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and

Background: Burnout in health care professionals (HCPs) results from exposure to psychosocial risks at work. Left unaddressed, burnout can lead to chronic health problems, increased staff turnover, reduced work hours, absenteeism, and early retirement from clinical practice, thus impacting patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force (RTF) was established in December 2019 to support the well-being of oncology HCPs globally. This ESMO RTF position paper aims to provide a set of recommendations to optimise well-being and mitigate burnout in oncology, and to help individuals and institutions maintain the delivery of optimal cancer care., Design: Recommendations were developed by a diverse multinational panel of interprofessional experts based on the key findings from three previously reported ESMO RTF surveys., Results: Several recurrent work-related psychosocial risks in oncology were identified; in particular, concerns about workload and professional development. The need for flexible work patterns, continued use of virtual resources, well-being resources, and targeted support for at-risk groups were highlighted as key considerations to safeguard HCPs' health and prevent burnout. In total, 11 recommendations relating to three priority themes were developed: (i) information and training; (ii) resources; (iii) activism and advocacy., Conclusion: Optimising the well-being of oncology HCPs is essential for the provision of high-quality, sustainable care for patients globally. The ESMO RTF will continue its mission and is rolling out several initiatives and activities to support the implementation of these recommendations., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL-ACT) has consistently shown efficacy in advanced melanoma. New results in the field provide now the opportunity to assess overall survival (OS) after TIL-ACT and to examine the effect of prior anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] therapy on its efficacy., Methods: A comprehensive search was conducted in PubMed up to 29 February 2024. Ιn this meta-analysis we focused on studies including high-dose interleukin 2, doubling the patient numbers from our previous meta-analysis conducted up to December 2018 and using OS as the primary endpoint. Objective response rate (ORR), complete response rate (CRR), and duration of response were secondary endpoints. Findings are synthesized using tables, Kaplan-Meier plots, and forest plots. Pooled estimates for ORR and CRR were derived from fixed or random effects models., Results: A total of 13 high-dose interleukin 2 studies were included in this updated meta-analysis, with OS information available for 617 patients. No difference was found in median OS between studies with prior anti-PD-(L)1 treatment {n = 238; 17.5 months [95% confidence interval (CI) 13.8-20.5 months]} and without [n = 379; 16.3 months (95% CI 14.2-20.6 months)] (log-rank P = 0.53). ORR was estimated to be 34% (95% CI 16%-52%) and 44% (95% CI 37%-51%), for the studies with and without prior anti-PD-(L)1, respectively. The pooled estimate for CRR was 10% for both groups. No statistically significant difference was observed between the two groups, either for ORR (P = 0.15) or CRR (P = 0.45)., Conclusions: Prior anti-PD-(L)1 treatment has no effect on the clinical response or survival benefit from TIL-ACT in advanced cutaneous melanoma. The benefit of TIL therapy in the second-line setting is also present after anti-PD-(L)1 treatment. Our data reinforce the evidence that TIL-ACT should be considered as a treatment of choice in second line for metastatic melanoma patients failing anti-PD-(L)1 therapy., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions., Methods: We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to BRAF mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response., Results: With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab., Conclusions: The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)., (Copyright © 2024 Massachusetts Medical Society.)

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 ., (© 2024. The Author(s).)

Introduction: Research has confirmed the safety and comparable seroconversion rates following SARS-CoV-2 vaccination in patients with solid cancers. However, the impact of cancer treatment on vaccine-induced T cell responses remains poorly understood., Methods: In this study, we expand on previous findings within the VOICE trial by evaluating the functional and phenotypic composition of mRNA-1273-induced T cell responses in patients with solid tumors undergoing immunotherapy, chemotherapy, or both, compared to individuals without cancer. We conducted an ELISpot analysis on 386 participants to assess spike-specific T cell responses 28 days after full vaccination. Further in-depth characterization of using flow cytometry was performed on a subset of 63 participants to analyze the functional phenotype and differentiation state of spike-specific T cell responses., Results: ELISpot analysis showed robust induction of spike-specific T cell responses across all treatment groups, with response rates ranging from 75% to 80%. Flow cytometry analysis revealed a distinctive cytokine production pattern across cohorts, with CD4 T cells producing IFNγ, TNF, and IL-2, and CD8 T cells producing IFNγ, TNF, and CCL4. Variations were observed in the proportion of monofunctional CD4 T cells producing TNF, particularly higher in individuals without cancer and patients treated with chemotherapy alone, while those treated with immunotherapy or chemoimmunotherapy predominantly produced IFNγ. Despite these differences, polyfunctional spike-specific memory CD4 and CD8 T cell responses were comparable across cohorts. Notably, immunotherapy-treated patients exhibited an expansion of spike-specific CD4 T cells with a terminally differentiated effector memory phenotype., Discussion: These findings demonstrate that systemic treatment in patients with solid tumors does not compromise the quality of polyfunctional mRNA-1273-induced T cell responses. This underscores the importance of COVID-19 vaccination in patients with solid cancers undergoing systemic treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gangaev, van Sleen, Brandhorst, Hoefakker, Prajapati, Singh, Boerma, van der Heiden, Oosting, van der Veldt, Hiltermann, GeurtsvanKessel, Dingemans, Smit, de Vries, Haanen, Kvistborg and van Baarle.)

Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has proven highly effective for treating solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy for yet unknown reasons. Defining markers that correlate with high tumor-reactivity of the autologous TIL products is thus key for achieving better tailored immunotherapies. We questioned whether the composition of immune cell infiltrates correlated with the tumor-reactivity of expanded TIL products. Unbiased flow cytometry analysis of immune cell infiltrates of 26 early-stage and 20 late-stage NSCLC tumor lesions was used for correlations with the T cell differentiation and activation status, and with the expansion rate and anti-tumor response of generated TIL products. The composition of tumor immune infiltrates was highly variable between patients. Spearman's Rank Correlation revealed that high B cell infiltration negatively correlated with the tumor-reactivity of the patient's expanded TIL products, as defined by cytokine production upon exposure to autologous tumor digest. In-depth analysis revealed that tumor lesions with high B cell infiltrates contained tertiary lymphoid structure (TLS)-related immune infiltrates, including BCL6 + antibody-secreting B cells, IgD + BCL6 + B cells and CXCR5 + BLC6 + CD4 + T cells, and higher percentages of naïve CD8 + T cells. In conclusion, the composition of immune cell infiltrates in NSCLC tumors associates with the functionality of the expanded TIL product. Our findings may thus help improve patient selection for TIL therapy., Competing Interests: MCW declares to have a consulting role for ONO therapeutics. JH declares to have advisory roles for AstraZeneca, Achilles Therapeutics, BioNTech, CureVac, Immunocore, Iovance Bio, Instil Bio, MSD, Molecular Partners, Neogene Therapeutics, Novartis, Roche, Sanofi, T-Knife, Third Rock Ventures. Grant support from Amgen, Asher Bio, BioNTech, BMS, Novartis, Sastra Cell Therapy. Stock options: Neogene Therapeutics, Sastra Cell Therapy. KM declares to have grant support from AstraZeneca, Amgen, Abbvie, BMS, Bayer, Boehringer Ingelheim, Benecke, Delfi, Diaceutics, Lilly, Merck, MSD, PGDx, Pfizer, Roche, Takeda, of which none are related to this work. All other authors declare to have no competing interest., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: This prospective study evaluates the biodistribution of 18 F-FLT PET in patients with advanced melanoma before and after treatment with BRAF/MEK inhibitors., Patients and Methods: Eighteen BRAF-positive unresectable stage IIIc or IV melanoma patients referred for 18 F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18 F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified., Results: Baseline interpatient 18 F-FLT uptake had a coefficient-of-variation between 17.5% and 21.5%. During treatment, liver uptake increased (SUV meanBL = 4.86 ± 0.98, SUV meanD14 = 6.31 ± 1.36, P < 0.001) and bone marrow uptake decreased (SUV meanBL = 7.67 ± 1.65, SUV meanD14 = 6.78 ± 1.19, P < 0.025). Both changes were unrelated to baseline metabolic tumor volume or tumor response., Conclusions: To assess 18 F-FLT PET, both liver and bone marrow uptake may be used as normal tissue references at baseline, but 18 F-FLT biodistribution significantly changes in longitudinal response studies when treated with BRAF/MEK inhibitors., Competing Interests: Conflicts of interest and sources of funding: A.J.M.v.d.E. received study grant from Sanofi, Roche, Bristol Myers Squibb, TEVA, and Idera; received travel expenses coverage from MSD Oncology, Roche, Pfizer, and Sanofi; received speaker honoraria from Bristol Myers Squibb and Novartis; and is part of the advisory board of Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, and Merck, Pierre Fabre. E.K. has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly, and Bayer, all paid to institute, as well as received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis, and Pierre Fabre. F.Y.F.L.d.V. received research grant from Foundation STOPBraintumors.org , Bristol Myers Squibb, Novartis, Servier, CureVac, and EORTC, all paid to institute. J.B.A.G.H. has advisory roles for Bristol Myers Squibb, CureVac, GSK, Ipsen, Iovance Biotherapeutics, Imcyse, Merck Serono, Molecular Partners, MSD, Novartis, Pfizer, Roche, Sanofi, and Third Rock Ventures; is a member of SAB of Achilles Tx, BioNTech, Gadeta, Immunocore, Instil Bio, PokeAcell, Scenic, T-Knife, and Neogene Tx, all paid to institute except Neogene Tx and Scenic; and received grant support from Amgen, Asher Bio, BioNTech, Bristol Myers Squibb, MSD, Novartis, and Sastra Cell Therapy, all paid to institute. The other authors declare no conflicts of interest. This work was supported by an unrestricted grant by Roche Medical B.V. The company has approved the design of the study and provided cobimetinib free of charge. The company has no role in collection, analysis, and interpretation of data or in writing the manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi., Patients and Methods: Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies., Results: Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at the time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients., Conclusions: Intermittent treatment with vorinostat in patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%)., (©2024 American Association for Cancer Research.)

Background: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs., Methods: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression., Results: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HR adj 1.14; 95 %CI 1.01-1.29; HR adj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HR adj 1.32; 95 %CI 1.02-1.72) and OS (HR adj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone., Conclusions: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GAPH reports consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Merck Sharp and Dome, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research funding from Bristol-Myers Squibb and Seerave. All paid to institution. MJBA reports consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Novartis, Merck Sharp and Dome, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas and Bayer, and received research funding from Merck-Pfizer. All paid to institution. KC reports consultancy fees from Eli Lilly AbbVie and Pfizer. ATJM has received fees from AbbVie, Actelion, CSL Behring, Experf, Novartis, and Shire and declares speaking fees from AstraZeneca, Sanofi-Aventis and Bristol-Myers Squibb. CUB reports consulting/advisory relationships with AstraZeneca, Bristol-Myers Squibb, GenMab, GSK, Lilly, Merck Sharp and Dome, Novartis, Pfizer, Pierre Fabre, Roche and Third Rock Ventures, and received research funding from 4SC, Bristol-Myers Squibb, NanoString and Novartis. All paid to institution. His is co-founder of and owns shares in Immagene BV and Signature Oncology, and is inventor on several related patents (including submitted): WO 2021/177822 A1, N2027907 and P091040NL2. SA reports consulting/advisory relationships with Merck Sharp and Dome, Sanofi, Roche, Bristol-Myers Squibb, Pfizer, Ipsen and Galapagos. All paid to institution. DP reports consultancy/advisory relationships with Pierre Fabre and Novartis. Partly paid to intstitution. EK reports consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to institute. ML reports consultancy/advisory relationships with Bristol-Myers Squibb and Janssen-Cilag B.V. All paid to institution. AMMvdV reports consultancy/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Sanofi, Pfizer, Novartis, Roche, Eisai, Merck, Pierre Fabre and Ipsen. All paid to institution. JBAGH reports consultancy/advisory relationships with Achillus Tx, AstraZenica, BioNTech, Bristol-Myers Squibb, CureVac, GlaxoSmithKline, Imcyse, Iovance Bio, Instil Bio, Ipsen, Merck, Merck Sharp and Dome, Molecular Partners, Neogene TX, Novartis, Pfizer, PokeAcell, Roche, Sanofi, Scenic, T-Knife and TRV, and received research funding from Amgen, Bristol-Myers Squibb, BioNTech, Merck Sharp and Dome, Novartis and Sastra Cell Therapy. All paid to institution. KPMS reports consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis, Sairopa. She received honoraria from Novartis and Merck Sharp and Dome, and research funding from TigaTx, Bristol Myers Squibb, Philips and Genmab. All paid to institution. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70- targeted allogeneic CAR T cells. Significance: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1., Materials and Methods: This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies., Results: 169 irAEs were experienced by 86/143 patients (137 grades 1-2, 32 grades 3-4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597)., Conclusion: The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction., Competing Interests: Competing interests: EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to the institute. JH received compensation for advisory roles for Achilles Therapeutics, AZ, BioNTech, BMS, CureVac, Eisai, Gadeta, Imcyse, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Scenic, Third Rock Ventures, and T-knife, and has received grants (all paid to the institute) from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis, Neogene Therapeutics and Sastra Cell Therapy. All other authors declare to have no competing interest with respect to this manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)

Introduction: Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center., Methods: All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan-Meier method., Results: Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti-PD-1 plus anti-CTLA-4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes-related ketoacidosis (n = 8), immune-related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2-6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0-NA)., Conclusion: The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long-term survival., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10-7.67, Cox P = 2.63e-05) and PFS (HR = 3.72, 95% CI 2.06-6.73, Cox P = 1.38e-05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24-6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16-3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2-3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08-3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH., (© 2024. The Author(s).)

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

T cell receptor (TCR) gene therapy is a potent form of cellular immunotherapy in which patient T cells are genetically engineered to express TCRs with defined tumor reactivity. However, the isolation of therapeutic TCRs is complicated by both the general scarcity of tumor-specific T cells among patient T cell repertoires and the patient-specific nature of T cell epitopes expressed on tumors. Here we describe a high-throughput, personalized TCR discovery pipeline that enables the assembly of complex synthetic TCR libraries in a one-pot reaction, followed by pooled expression in reporter T cells and functional genetic screening against patient-derived tumor or antigen-presenting cells. We applied the method to screen thousands of tumor-infiltrating lymphocyte (TIL)-derived TCRs from multiple patients and identified dozens of CD4 + and CD8 + T-cell-derived TCRs with potent tumor reactivity, including TCRs that recognized patient-specific neoantigens., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC)., Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS)., Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0-62.4) and 59.6% (95% CI, 51.3-67.5), respectively. ORR was 35.1% (95% CI, 27.5-43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%)., Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice., Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi., Competing Interests: John B.A.G. Haanen reports research grants to the institution from Asher Bio, Amgen, BioNTech, Bristol Myers Squibb, Novartis, and Sastra Cell Therapy, consultation fees to the institution from Achilles Tx, AstraZeneca, BioNTech, Bristol Myers Squibb, CureVac, Eisai, GlaxoSmithKline, Imcyse, Immunocore, Instil Bio, Iovance Bio, Merck, Merck Sharp & Dohme, Neogene Tx, Novartis, Obsidian Tx, Roche, Sanofi, Sastra Cell Therapy, Third Rock Ventures, and T-Knife, and stock options from Neogene Tx and Sastra Cell Therapy. Mathilde Jalving received compensation to the institution for advisory roles for Pierre Fabre, Merck, and Novartis. Lot A. Devriese received compensation to the institution for advisory roles and education for Bristol Myers Squibb, Merck Sharp & Dohme, and Incyte. Astrid A.M. van der Veldt received compensation to the institution for advisory roles for Bristol Myers Squibb, Merck Sharp & Dohme, Eisai, Ipsen, Novartis, Pierre Fabre, Pfizer, Roche, and Sanofi. Maureen J.B. Aarts reports research grants to the institution from Merck-Pfizer and consultation fees to the institution from being on the advisory board from Amgen, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, and Bayer. Carla M.L. van Herpen reports research grants to the institution from Astra Zeneca, Bayer, Bristol Myers Squibb, Elevar, Ipsen, Merck Sharp & Dohme, Merck, Novartis, and Sanofi, payments for lectures to the institution from ICCR, NIFU, RIVM, Roije Congressen, Nederlands Paramedisch Instituut, Elevar, and Uitgeverij Jaap, and payments to the institution for participating on an advisory board to the institution from Elevar. Mariette Labots received compensation to the institution for education for Bristol Myers Squibb and Janssen. Sahar Barjesteh van Waalwijk van Doorn-Khosrovani reports the PRIME-ROSE—A European precision cancer medicine trial network and implementation initiative funded by the EU Cancer Mission; grant no. 101104269 paid to the Leiden University Medical Center and travel expenses for attending meetings at the Nordic Precision Medicine Forum and Center for Innovation in Regulatory Science. Egbert F. Smit reports compensation to the institution for advisory roles at AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, Merck Sharp & Dohme, Roche, Sanofi, and Takeda, personal compensation for education from Boehringer Ingelheim and Daiichi Sankyo, and compensation to the institution for participation in the data safety monitoring board of DSI. The other authors have no conflicts of interests to disclose., (© 2024 The Author(s).)

Abstract: Major progress in prolonging survival of patients with advanced melanoma has been made in the past decade because of the development and approval of immune checkpoint inhibitor and targeted therapies. However, for nonresponding or relapsing patients, their prognosis is still dismal. Based on clinical trial data, treatment with adoptive cell therapies holds great promise. In patients with metastatic melanoma progressing on or nonresponsive to single-agent anti-programmed cell death 1, infusion of tumor-infiltrating lymphocytes can produce responses in up to half of patients, with durable complete responses in up to 20%. Genetic modification of peripheral blood T cells with T-cell receptors derived from tumor-specific T cells, or with chimeric antigen receptors, has the potential to further improve treatment outcomes in this refractory population. In this review, we will discuss the historical development, current status, and future perspectives of adoptive T-cell therapies in melanoma., Competing Interests: Conflicts of Interest and Source of Funding: C.L. and S.K. have no conflicts of interest. The conflicts of interest for J.B.A.G.H. are as follows: advisory roles for AZ, Achilles Therapeutics, BioNTech, CureVac, Immunocore, Iovance Biotherapeutics, Instil Bio, MSD, Molecular Partners, Neogene Therapeutics, Novartis, Roche, Sanofi, T-Knife, and Third Rock Ventures; grant support from Amgen, Asher Bio, BioNTech, BMS, Novartis, and Sastra Cell Therapy; and stock options in Neogene Therapeutics and Sastra Cell Therapy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Immunotherapy with immune-checkpoint inhibitors (ICIs) and targeted therapy with BRAF and MEK inhibitors have revolutionized the treatment of melanoma over the past decade. Despite these breakthroughs, the 5-year survival rate of patients with advanced-stage melanoma is at most 50%, emphasizing the need for additional therapeutic strategies. Adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) is a therapeutic modality that has, in the past few years, demonstrated long-term clinical benefit in phase II/III trials involving patients with advanced-stage melanoma, including those with disease progression on ICIs and/or BRAF/MEK inhibitors. In this Review, we summarize the current status of TIL therapies for patients with advanced-stage melanoma, including potential upcoming marketing authorization, the characteristics of TIL therapy products, as well as future strategies that are expected to increase the efficacy of this promising cellular immunotherapy., (© 2024. Springer Nature Limited.)

The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non-T-cell-mediated and non-natural killer cell-mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes., Significance: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens. This article is featured in Selected Articles from This Issue, p. 384., (©2023 The Authors; Published by the American Association for Cancer Research.)

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88-1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73-2.38; p = 0.44). Grade 3-4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed., (© 2024. The Author(s).)

Background: Treatment with tumor-infiltrating lymphocytes (TILs) is rapidly evolving for patients with solid tumors. Following metastasectomy, TILs (autologous, intratumoral CD4+ and CD8+ T cells with the potential to recognize tumor-associated antigens) are isolated and non-specifically expanded ex vivo in the presence of interleukin-2 (IL-2). Subsequently, the TILs are adoptively transferred to the patients after a preconditioning non-myeloablative, lymphodepleting chemotherapy regimen, followed by administration of high-dose (HD) IL-2. Here, we provide an overview of known cardiac risks associated with TIL treatment and report on seven patients presenting with cardiac symptoms, all with different clinical course and diagnostic findings during treatment with lymphodepleting chemotherapy, TIL, and HD IL-2, and propose a set of clinical recommendations for diagnosis and management of these symptoms., Patients and Methods: This single-center, retrospective study included selected patients who experienced TIL treatment-related cardiac symptoms at the Netherlands Cancer Institute. In addition, 12 patients were included who received TIL in the clinical trial setting without experiencing cardiac symptoms, from whom complete cardiac biomarker follow-up during treatment was available [creatine kinase (CK), CK-myocardial band, troponin T and N-terminal pro-B-type natriuretic peptide]., Results: Within our TIL patient population, seven illustrative cases were chosen from the patients who developed symptoms suspected of severe cardiotoxicity: myocarditis, myocardial infarction, peri-myocarditis, atrial fibrillation, acute dyspnea, and two cases of heart failure. An overview of their clinical course, diagnostics carried out, and management of the symptoms is provided., Conclusions: In the absence of evidence-based guidelines for the treatment of TIL therapy-associated cardiotoxicity, we provided an overview of literature, case descriptions, and recommendations for diagnosis and management to help physicians in daily practice, as the number of patients qualifying for TIL treatment is rapidly increasing., Competing Interests: Disclosure AWS received a speakers fee from Philips. SK participated in an advisory board for Regeneron. JBAGH has provided consultation, attended advisory boards, and/or provided lectures for BMS, CureVac, GSK, Imcyse, Iovance Bio, Instil Bio, Immunocore, Ipsen, Merck Serono, MSD, Molecular Partners, Novartis, Pfizer, Roche/Genentech, Sanofi, Scenic, and Third Rock Ventures; has participated in the SAB of Achilles Tx, BioNTech US, Instil Bio, PokeAcell, T-Knife, Scenic and Neogene Therapeutics, and through this the NKI has received grant support from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis, Sastra Cell Therapy. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The aims of this study were to investigate whether (early) PERCIST response monitoring with 18 F-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or IV melanoma patients treated with BRAF/MEK inhibitor (MEKi) and to define dissemination patterns at progression with a lesion-based evaluation in direct comparison to baseline to improve our understanding of 18 F-FDG PET/CT during BRAF/MEKi., Patients and Methods: This prospective multicenter single-arm study included 70 patients with unresectable stage III/IV BRAF -mutated melanoma who underwent contrast-enhanced CT and 18 F-FDG PET/CT at baseline and 2 and 7 weeks during treatment with vemurafenib plus cobimetinib and at progression if possible. Tumor response assessment was done with RECIST1.1 and PERCIST. Follow-up PET/CT scans were visually compared with baseline to assess dissemination patterns., Results: Using RECIST1.1, PFS was not significantly different between the response groups ( P = 0.26). At 2 weeks, PERCIST median PFS was 15.7 months for patients with complete metabolic response (CMR) versus 8.3 months for non-CMR ( P = 0.035). The hazards ratio (HR) for progression/death in non-CMR versus CMR was 1.99 (95% confidence interval [CI], 1.03-3.84; P = 0.040) and 1.77 (95% CI, 0.91-3.43; P = 0.0935) when adjusting for lactate dehydrogenase (LDH). At 7 weeks, median PFS for PERCIST CMR was 16.7 months versus 8.5 months for non-CMR ( P = 0.0003). The HR for progression/death in the non-CMR group was significantly increased (HR, 2.94; 95% CI, 1.60-5.40; P = 0.0005), even when adjusting for LDH (HR, 2.65; 95% CI, 1.43-4.91; P = 0.0020). At week 7, 18 F-FDG PET/CT was false-positive in all 4 (6%) patients with new FDG-avid lesions but CMR of known metastases. When 18 F-FDG PET/CT was performed at progressive disease, 18/22 (82%) patients had progression of known metastases with or without new 18 F-FDG-avid lesions., Conclusions: This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early 18 F-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new 18 F-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease., Competing Interests: Conflicts of interest and sources of funding: The REPOSIT study is supported by an unrestricted grant by Roche Medical B.V. The company has approved the design of the study and provided cobimetinib free of charge. The company has no role in collection, analysis, and interpretation of data or in writing the article. A.J.M.v.d.E. received study grant from Sanofi, Roche, Bristol Myers Squibb, TEVA, and Idera; received travel expenses coverage from MSD Oncology, Roche, Pfizer, and Sanofi; received speaker honoraria from Bristol Myers Squibb and Novartis; and is part of the advisory board of Bristol Myers Squibb, MSD Oncology, Amgen, Roche, Novartis, Sanofi, Pfizer, Ipsen, Merck, and Pierre Fabre. E.W.K. has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly, and Bayer, all paid to the institute; and received research grants not related to this article from Bristol Myers Squibb, Delcath, Novartis, and Pierre Fabre. G.A.P.H. has consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, and Pierre Fabre, all paid to the institute; and received research grants from Bristol Myers Squibb and Seerave, all paid to the institute. M.J.B.A. has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, and Bayer, and research grants from Merck-Pfizer, all paid to the institute and not related to current work. F.Y.F.L.d.V. received research grant from Foundation STOPBraintumors.org , Bristol Myers Squibb, Novartis, Servier, CureVac, and EORTC, all paid to the institute. A.A.M.v.d.V. has consultancy roles (all paid to the institute) for Bristol Myers Squibb, MSD, Roche, Sanofi, Novartis, Pierre Fabre, Merck, Ipsen, Eisai, and Pfizer, all paid to the institute. J.B.A.G.H. has advisory roles for Bristol Myers Squibb, CureVac, GSK, Ipsen, Iovance Biotherapeutics, Imcyse, Merck Serono, Molecular Partners, MSD, Novartis, Pfizer, Roche, Sanofi, and Third Rock Ventures; is a member of SAB of Achilles Tx, BioNTech, Gadeta, Immunocore, Instil Bio, PokeAcell, Scenic, T-Knife, and Neogene Tx, all paid to the institute except Neogene Tx and Scenic; and received grant support from Amgen, Asher Bio, BioNTech, Bristol Myers Squibb, MSD, Novartis, and Sastra Cell Therapy, all paid to the institute. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1) + CD8 + T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 ., (© 2024. The Author(s).)

Introduction: Naked DNA vaccination could be a powerful and safe strategy to mount antigen-specific cellular immunity. We designed a phase I clinical trial to investigate the toxicity of naked DNA vaccines encoding CD8+ T-cell epitope from tumor-associated antigen MART-1 in patients with advanced melanoma., Methods: This dose escalating phase Ia clinical trial investigates the toxicity and immunological response upon naked DNA vaccines encoding a CD8+ T-cell epitope from the tumor-associated antigen MART-1, genetically linked to the gene encoding domain 1 of subunit-tetanus toxin fragment C in patients with advanced melanoma (inoperable stage IIIC-IV, AJCC 7th edition). The vaccine was administrated via intradermal application using a permanent make-up or tattoo device. Safety was monitored according to CTCAE v.3.0 and skin biopsies and blood samples were obtained for immunologic monitoring., Results: Nine pretreated, HLA-A*0201-positive patients with advanced melanoma expressing MART-1 and MHC class I, with a good performance status, and adequate organ function, were included. With a median follow-up of 5.9 months, DNA vaccination was safe, without treatment-related deaths. Common treatment-emergent adverse events of any grade were dermatologic reactions at the vaccination site (100%) and pain (56%). One patient experienced grade 4 toxicity, most likely related to tumor progression. One patient (11%) achieved stable disease, lasting 353 days. Immune analysis showed no increase in vaccine-induced T cell response in peripheral blood of 5 patients, but did show a MART-1 specific CD8+ T cell response at the tattoo administration site. The maximum dose administered was 2 mg due to lack of clinical activity., Conclusion: We showed that the developed DNA vaccine, applied using a novel intradermal application strategy, can be administered safely. Further research with improved vaccine formats is required to show possible clinical benefit of DNA vaccination., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab., (Copyright © 2023 Massachusetts Medical Society.)

The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278 ., (© 2023. The Author(s).)

To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in treatment-naive head and neck squamous cell carcinoma, we analyzed primary tumor immune infiltrates from responding and nonresponding patients. At baseline, a higher ratio between active (4-1BB/OX40+) and inactive regulatory CD4+ T cells was associated with immunotherapy response. Furthermore, upon therapy, this active regulatory T-cell (Treg) population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells displayed decreased expression of activity and dysfunction-related genes in responding patients, whereas in clinical nonresponders, natural killer cells showed an increased cytotoxic profile early upon treatment. These data reveal immunologic changes in response to dual PD-1/CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive Treg and CD8+ T-cell compartments in responding patients, and indicate that the presence of activated Tregs at baseline may be associated with response., Significance: In head and neck squamous cell carcinoma, neoadjuvant PD-1/CTLA4 blockade has shown substantial response rates (20%-35%). As recognition of tumor antigens by T cells appears to be a critical driver of therapy response, a better understanding of alterations in T-cell state that are associated with response and resistance is of importance. This article is featured in Selected Articles from This Issue, p. 2109., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Patients with advanced melanoma refractory to first-line treatment have a need for effective second-line treatment options. A recent phase 3 trial showed promising results for adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) as second-line therapy in patients with advanced melanoma. However, it remains unknown how patients and their partners experience TIL therapy, which is key to evaluate and improve the quality of care., Methods: Semi-structured interviews about the experience of TIL therapy were conducted with patients with advanced melanoma and their partners 2-4 weeks post-treatment (short term) and >6 months after treatment (long term)., Results: In total, 25 interviews were conducted with advanced melanoma patients treated with TIL (n=13) and their partners (n=12), with the majority being short-term interviews (n=17). Overall, patients and partners experienced TIL therapy as intense (uncertainty of successful TIL culture, multiple treatment-related toxicities, and extensive hospitalization). Patients and partners with young children or other caregiving responsibilities encountered the most challenges during TIL therapy. All patients, however, reported a recovery of all treatment-related toxicities within 2-4 weeks (except fatigue)., Conclusion: Clinical data justify the role of TIL therapy in the treatment of advanced melanoma. With the distinct nature of TIL therapy compared to the current standard of care, we have provided patient-centered recommendations that will further enhance the quality of TIL therapy., Implications for Cancer Survivors: As more patients with advanced melanoma are expected to receive TIL therapy in the future, our findings could be incorporated into survivorship care plans for this novel group of advanced melanoma survivors treated with TIL., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Upfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories., Objective: To investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN., Design Setting and Participants: This was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED., Outcome Measurements and Statistical Analysis: We measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined., Results and Limitations: At median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued ( n  = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% ( p  = 0.675) and 3-yr CSS was 100% versus 70% ( p  = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo., Conclusions: CN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety., Patient Summary: In our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival., (© 2023 The Authors.)

Background: Although cutaneous squamous cell carcinoma (cSCC) is common, lymph node metastases are relatively rare and are usually treated with lymph node dissection (LND). The aim of this study was to describe the clinical course and prognosis after LND for cSCC at all anatomical locations., Methods: A retrospective search at three centres was performed to identify patients with lymph node metastases of cSCC who were treated with LND. Prognostic factors were identified by uni- and multivariable analysis., Results: A total of 268 patients were identified with a median age of 74. All lymph node metastases were treated with LND, and 65% of the patients received adjuvant radiotherapy. After LND, 35% developed recurrent disease both locoregionally and distantly. Patients with more than one positive lymph node had an increased risk for recurrent disease. 165 (62%) patients died during follow-up of whom 77 (29%) due to cSCC. The 5-year OS- and DSS rate were 36% and 52%, respectively. Disease-specific survival was significantly worse in immunosuppressed patients, patients with primary tumors >2cm and patients with more than one positive lymph node., Conclusions: This study shows that LND for patients with lymph node metastases of cSCC leads to a 5-year DSS of 52%. After LND, approximately one-third of the patients develop recurrent disease (locoregional and/or distant), which underscores the need for better systemic treatment options for locally advanced cSCC. The size of the primary tumor, more than one positive lymph node, and immunosuppression are independent predictors for risk of recurrence and disease-specific survival after LND for cSCC., (© 2023. The Author(s).)