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In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy. Significance: Autologous tumor-infiltrating lymphocyte therapy lifileucel was administered to 28 patients with heavily pretreated metastatic non-small cell lung cancer (mNSCLC). Responses were observed in patients with driver mutations, and various tumor mutational burdens and PD-L1 expression, potentially addressing an unmet medical need in patients with mNSCLC refractory to prior therapy. See related commentary by Lotze et al., p. 1366., (©2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce., Methods: We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria., Results: 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013)., Conclusion: This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy., Competing Interests: Competing interests: JLA reports meeting travel support from Vifor Pharma. NP reports he has served as a speaker for Allergan, Bristol Myers Squibb, Falk, Ferring, Janssen, Pfizer, Tillotts, and Takeda, and as a consultant and/or an advisory board member for AbbVie, Allergan, Celgene, Bristol Myers Squibb, Ferring, and Vifor Pharma. DJP received lecture fees from ViiV Healthcare, EISAI, BMS, Roche, Bayer Healthcare and travel expenses from BMS, MSD and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, AstraZeneca, DaVolterra; received research funding (to institution) from MSD, BMS, and Biognosys. SMC reports travel grant from Tesaro and honoraria for educational events from BMS and GSK. JL reports institution grants from Achilles therapeutics, BMS, Merck Sorono, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo and Pharmacyclics; consulting fees from Iovance, Boston Biomedical, Pfizer, BMS, GSK, Novartis, Incyte, Immunocore, YKT Global, iOnctura and Apple Tree; honoraria from Roche, Novartis, iOnctura, BMS, Pfizer, Incyte, Dynavax, CRUK, GSK, Eisai, Merck, TouchIME and Touch Experts and support for meeting attendance and/or travel from BMS, iOnctura, Roche, Pfizer, Incyte, Merck, Novartis, Pierre Fabre, BUG, ESMO, AIM, AstraZeneca, NCRI, Syneos Health, EUSA, KCA, Bioevents, MedConcept, GSK and RVMais. ST reports grants or contracts from Cancer Research UK (grant reference number C50947/A18176), The National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), The Kidney and Melanoma Cancer Fund of the Royal Marsden Cancer Charity, The Rosetrees Trust (grant reference number A2204) and Ventana Medical Systems Inc (grant reference numbers 10467 and 10530), honoraria from Jules Bordet Institute, Erasmus, Open Health and MD Anderson, support for attending meetings and/or travel from Jules Bordet Institute, ESMO, SMR, Broad, KCA, IFOM, EORTC, ASCO, Ventana, Roche, Institute of Molecular Medicine, KTH Sweden, Pfizer, Erasmus, Systems biology, MD Anderson, WK Weiser, AACR, Research degrees Team, Melanoma Focus and SITC, patents Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. SP reports honoraria from BMS, MSD, Novartis, Amgen, Gritstone, Zelluna, Achilles, Enara Bio and GSK and travel support from BMS and MSD., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma., Competing Interests: SNK and JFS are founders and shareholders of Epsilogen Ltd. HJB is now employed through a fund provided by Epsilogen Ltd. The remaining 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 © 2021 Willsmore, Harris, Crescioli, Hussein, Kakkassery, Thapa, Cheung, Chauhan, Bax, Chenoweth, Laddach, Osborn, McCraw, Hoffmann, Nakamura, Geh, MacKenzie-Ross, Healy, Tsoka, Spicer, Papa, Barber, Lacy and Karagiannis.)

Indications for immune checkpoint inhibitor therapy are increasing. As the population ages, many patients receiving such drugs will be older adults. Such patients are under-represented in clinical trials, and therefore the safety of immune checkpoint inhibitors in this population has not been adequately assessed. A retrospective multicenter analysis of toxicities was performed in patients with advanced or metastatic solid cancers receiving anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies across three age cohorts (<65 years, 65-74 years and ≥75 years) using univariable and multivariable analyzes. Eligible patients (n=448) were divided into age cohorts: <65 years (n=185), 65-74 years (n=154) and ≥75 years (n=109). Fewer patients in the oldest cohort (7.3%) received an anti-CTLA4 antibody containing regimen compared with the younger cohorts (21.1% and 17.5%). There was no significant difference overall in all grade or ≥G3 toxicities between age cohorts. Significantly fewer patients in the older (65-74 years and ≥75 years) age cohorts discontinued treatment because of toxicity (10.1% and 7.4%) compared with in the <65 years cohort (20.5%; p=0.006). Using logistic regression, only treatment type (ipilimumab containing) was significantly associated with all grade toxicity. However, there was a significantly lower incidence of all-grade endocrine toxicity in the oldest cohort (11.0%) compared with the youngest cohort (22.7%, p=0.02; OR 0.43, 95% CI 0.21 to 0.87), while all-grade dermatological toxicity showed the reverse trend (28.4% vs 18.9%; OR 1.85, 95% CI 1.04 to 3.30). Results were corroborated in the sensitivity analysis using only data from patients who received PD-1 inhibitor monotherapy. This multicenter, real-world cohort demonstrates that immune checkpoint inhibitor therapy is safe and well tolerated regardless of age, with no appreciable increase in adverse events in older adult patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

BackgroundImmune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.MethodsWe collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.ResultsICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.ConclusionsPatients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Background and aims: Cholestatic liver dysfunction is common in immune‐related hepatitis (irH) during treatment with immune checkpoint inhibitors (CPI) for malignancy. We investigated the spectrum of bile duct injury and associated natural history in this cohort. Method: Clinical, laboratory, radiological and histopathological data in patients with evidence of bile duct injury during CPI treatment from 2018 to 2020 was collected in three tertiary hospitals. Results: In this study, ten patients with confirmed bile duct disease were identified. Pembrolizumab was most commonly implicated (8/10). Median CPI cycles prior to bile duct injury was 6. Median alanine aminotransferase and alkaline phosphatase were 225 U/L and 1549 U/L respectively. Clinical jaundice was seen in 6/10 and radiological evidence of bile duct pathology in 8/10. Of five patients, who had liver biopsy, three cases (including two cases with normal MRCP) showed primary sclerosing cholangitis (PSC) like changes with periductal fibrosis. All patients were treated first‐line with prednisolone following cessation of CPI, three with mycophenolate mofetil and one with tacrolimus, with clinical response in four patients. Five patients died after a mean follow‐up of 27 weeks; cause of death was primarily related to progression of malignancy. Conclusion: Within this heterogeneous cohort, we identified that CPI‐related cholangiopathy responded poorly to immunosuppression and potentially progressed to bile duct loss. Thorough radiological and histological assessment is recommended, as identification of the cholangiopathy‐associated phenotype may permit more informed advice regarding prognosis. Further data is required to determine detailed immunological characterisation in order to identify individuals at an increased risk of developing cholangiopathy. [ABSTRACT FROM AUTHOR]

The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing 'old friends' in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success. [ABSTRACT FROM AUTHOR]