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Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury.Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury.Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined.Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC.Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627). [ABSTRACT FROM AUTHOR]

OBJECTIVES: The purpose of this study was to analyze the secretory cell population and distribution of MUC5B and MUC7 mucins in the sinus mucosa of pediatric patients with and without chronic rhinosinusitis (CRS). METHODS: Sinus mucosal specimens were collected at surgery in a pediatric tertiary care facility. Histologic, immunohistochemical, and morphometric analyses were performed on sinus mucosa of 20 children with CRS and 7 children without CRS. RESULTS: A significant increase in the area of submucosal glands was evident in the sinus mucosa of children with CRS as compared to controls. MUC5B and MUC7 mucins were expressed in the submucosal glands, as well as in goblet cells, in the sinus mucosa of both populations. No differences in MUC5B or MUC7 expression were observed when mucin expression was normalized to glandular area. CONCLUSIONS: Children with CRS have an increased number of submucosal glands, indicating that glandular mucins contribute to mucus overproduction in CRS. MUC5B and MUC7 mucins, which have previously been considered only glandular mucins, are also expressed in goblet cells in the sinus mucosa. [ABSTRACT FROM AUTHOR]

Background: Patients with prior allogeneic stem cell transplant (alloSCT) are typically excluded from trials of chimeric antigen receptor (CAR) T cell therapies, because their engineered cells may include allogeneic T cells. Ciltacabtagene autoleucel (cilta-cel) demonstrated early, deep, durable responses and manageable safety in heavily pretreated relapsed/refractory multiple myeloma patients. We retrospectively analyzed patients who received alloSCT prior to cilta-cel in CARTITUDE-1., Patients and Methods: Patients eligible for CARTITUDE-1 were ≥18 years, had ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and had received a PI, IMiD, and anti-CD38 antibody. Patients with active graft-versus-host disease (GVHD) or had alloSCT within 6 months before apheresis were excluded. Patients received cilta-cel 5 to 7 days after lymphodepletion., Results: Patients (N = 7) received median 9 prior LOTs (range, 6-14); median time since alloSCT was 5.1 years (range, 2.7-6.2). At median follow-up 27.7 months after cilta-cel infusion, overall response rate was 85.7% (n = 6). The safety profile was generally consistent with patients without alloSCT as prior therapy (cytokine release syndrome, 85.7% vs. 95.6%, respectively; immune effector cell-associated neurotoxicity syndrome, 14.3% vs. 16.7%). One patient with prior alloSCT had grade 3 movement and neurocognitive treatment-emergent adverse events/parkinsonism. No GVHD cases were reported. Two patients died due to adverse events (treatment-related lung abscess; unrelated liver failure)., Conclusion: Cilta-cel efficacy and safety were comparable between CARTITUDE-1 patients with and without prior alloSCT. Additional studies are needed to fully elucidate the suitability of CAR-T cell therapy in the post-alloSCT setting., Competing Interests: Disclosure M. Htut consulted and served on advisory committees for and received travel funding from Millennium; and received research funding from Judy and Bernard Briskin Center for Multiple Myeloma Research (Inst) and BMS (Inst). B. Dhakal consulted and served on advisory committees for Amgen, Takeda, Janssen, GlaxoSmithKline, Natera, and Sanofi; received honoraria from Celgene, Karyopharm Therapeutics, Sanofi, and GlaxoSmithKline; and received research funding from Amgen, Janssen, and GlaxoSmithKline. A.D. Cohen consulted and served on advisory committees for Celgene, Janssen Oncology, Oncopeptides, Takeda, Seattle Genetics, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, AstraZeneca, and Roche/Genentech; received research funding from Novartis (Inst) and GlaxoSmithKline (Inst); has patents related to CAR-T cells and biomarkers of cytokine release syndrome; has given expert testimony for Janssen Oncology; and received travel funding from GlaxoSmithKline, Takeda, Celgene, and Janssen Oncology. T. Martin consulted and served on advisory committees for GlaxoSmithKline and Legend Biotech USA Inc. and received research funding from Sanofi (Inst), Amgen (Inst), and Janssen Oncology (Inst). J.G. Berdeja consulted and served on advisory committees for Takeda (Inst), Bristol-Myers Squibb (Inst), CRISPR Therapeutics (Inst), Celgene (Inst), Kite, a Gilead company (Inst), Janssen (Inst), Legend Biotech (Inst), Secura Bio (Inst), and Bluebird Bio (Inst); and received research funding from Celgene (Inst), Takeda (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), Janssen (Inst), Novartis (Inst), AbbVie (Inst), Bluebird Bio (Inst), Teva (Inst), Genentech/Roche (Inst), Poseida Therapeutics (Inst), Sanofi (Inst), Acetylon Pharmaceuticals (Inst), Lilly (Inst), Celularity (Inst), CRISPR Therapeutics (Inst), EMD Serono (Inst), Ichnos Sciences (Inst), GlaxoSmithKline (Inst), and Incyte (Inst). S.Z. Usmani consulted and served on advisory committees for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GlaxoSmithKline, Karyopharm Therapeutics, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and Bristol-Myers Squibb/Celgene; served on speakers’ bureaus for Takeda, Amgen, Janssen Oncology, Sanofi, and Bristol-Myers Squibb/Celgene; and received research funding from Celgene, Array BioPharma, Janssen Oncology, Pharmacyclics, Sanofi, Bristol-Myers Squibb, Amgen, Seattle Genetics, Merck, SkylineDx, and GlaxoSmithKline. M. Agha owns stock in GenCART, Inc. D. Madduri is employed by Janssen Oncology; owns stock in Roivant; and consulted and served on advisory committees for Takeda, Janssen Oncology, Celgene, Legend Biotech USA Inc., GlaxoSmithKline, and Foundation Medicine. C.C. Jackson is employed by Janssen and owns stock in Janssen; and served as a consultant physician for Memorial Sloan Kettering Cancer Center. W. Deraedt, T.-m. Yeh, and X. Xu are employed by and own stock in Janssen. E. Zudaire is employed by, owns stock in, received travel funding from, and has patents pending with Janssen. L. Pacaud is employed by and owns stock in Legend Biotech USA Inc. M. Akram is employed by Legend Biotech USA, Inc. S. Jagannath consulted and served on advisory committees for Bristol-Myers Squibb, Janssen, Karyopharm Therapeutics, Legend Biotech USA Inc., Takeda, and Sanofi; and received travel funding from Bristol-Myers Squibb and Janssen., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease., Methods: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival., Results: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%)., Conclusions: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.)., (Copyright © 2023 Massachusetts Medical Society.)

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options., Competing Interests: Competing interests: MQ reports honoraria from Vertex and Novartis. MVD is on the advisory board for Janssen, Sanofi, and Lava Therapeutics. SC is on the science advisory board of SOBI. JLK reports consulting for Abbvie, BMS, and DSnC for Incyte. JMS reports employment, equity and stock options at Janssen. DM reports employment at Janssen Research & Development, being adjunct assistant professor at Mount Sinai Hospital, Icahn School of Medicine, and being on the consultancy/advisory board at Takeda, Celgene, BMS, GlaxoSmithKline, Legend, Janssen, Kinevant, and Foundation Medicine. CCJ is an employee of Janssen Research & Development and physician consultant at Memorial Sloan Kettering Cancer Center. EZ is an employee of Janssen Research & Development. AT-M is an employee of Janssen Research & Development and an adjunct assistant professor at Los Angeles County/University of Southern California. AB is an employee of Janssen Research & Development. MV is an employee of Janssen-Cilag GmbH. TN reports being an employee of Caribou Biosciences, Inc., in Berkeley, California. NL reports being a full-time employee of Janssen. LP is an employee at Legend Biotech., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups., Methods: Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee., Results: At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report., Conclusion: At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636., (© 2023 by The American Society of Hematology.)

Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma. Tumor-associated stromal cells processed collagen into glutamine, which was then released and internalized by cancer cells. Under chronic nutrient starvation, a condition driven by the high metabolic demand of tumors, cancer cells exploited glutamine to survive, an effect that could be reversed by blocking collagen uptake with TEM8 neutralizing antibodies. These studies reveal that cancer cells exploit collagen-consuming stromal cells for survival, exposing an important vulnerability across solid tumors with implications for developing improved anticancer therapy., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study., Methods: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability-high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter., Results: In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (C max ) ranged from 24.7 to 227.0 µg/mL; median time to C max ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1-high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC., Conclusions: The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors., Trial Registrations: NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016-002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017., (© 2022. The Author(s).)

B-cell maturation antigen (BCMA) is a target for the treatment of multiple myeloma with cytolytic therapies, such as chimeric antigen receptor T-cells or T-cell redirecting antibodies. To better understand the potential for "on-target/off-tumor" toxicity caused by BCMA-targeting cytolytic therapies in the brain, we investigated normal brain BCMA expression. An immunohistochemistry (IHC) assay using the E6D7B commercial monoclonal antibody was applied to 107 formalin-fixed, paraffin-embedded brain samples (cerebrum, basal ganglia, cerebellum, brainstem; 63 unique donors). Although immunoreactivity was observed in a small number of neurons in brain regions including the striatum, thalamus, midbrain, and medulla, this immunoreactivity was considered nonspecific and not reflective of BCMA expression because it was distinct from the membranous and Golgi-like pattern seen in positive control samples, was not replicated when a different IHC antibody (D6 clone) was used, and was not corroborated by in situ hybridization data. Analysis of RNA-sequencing data from 478 donors in the GTEx and Allen BrainSpan databases demonstrated low levels of BCMA RNA expression in the striatum of young donors with levels becoming negligible beyond 30 years of age. We concluded that BCMA protein is not present in normal adult human brain, and therefore on-target toxicity in the brain is unlikely.

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM., (© 2022. The Author(s).)

Background: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live-attenuated, double-deleted Listeria monocytogenes (LADD Lm)-based immunotherapy targeting 4 relevant prostate cancer antigens, was evaluated in a phase 1 study in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: Men with progressive mCRPC who had received ≥2 prior approved therapies were enrolled. Primary study objectives were to determine the recommended phase 2 dose (RP2D) and to evaluate the safety and immunogenicity of JNJ-809., Results: A total of 26 patients received JNJ-809 (1 × 10 8 CFU (n = 6); 1 × 10 9 CFU (n = 20)). No dose-limiting toxicities were reported, and 1 × 10 9 CFU was selected as the RP2D. The most common adverse events (AEs) reported were chills (92%), pyrexia (81%), and fatigue (62%). The most frequent grade ≥3 AEs were lymphopenia (27%) and hypertension (23%). Serious AEs were reported in 27% of patients including 1 patient with grade 3 intestinal obstruction. JNJ-809 transiently induced peripheral cytokines, including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of the 7 patients evaluable for T cell responses at the 1 × 10 9 CFU dose, evidence of post-treatment antigenic responses were observed in 6 to the Listeria antigen listeriolysin O and in 5 to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease in 13/25 response-evaluable patients. The study was terminated early as data collected were considered sufficient to evaluate safety and immunogenicity., Conclusions: JNJ-809 has manageable safety consistent with other LADD Lm-based therapies. Limited antigen-specific immune responses were observed, which did not translate into objective clinical responses., (© 2021. The Author(s).)

Background: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis., Methods: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10 6 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207., Findings: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10 6 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events., Interpretation: A single cilta-cel infusion at the target dose of 0·75 × 10 6 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions., Funding: Janssen Research & Development and Legend Biotech., Competing Interests: Declaration of interests JGB receives research funding from AbbVie, Amgen, Acetylon, Bluebird, Bristol Myers Squibb, Celgene, Cellularity, Constellation, CRISPR Therapeutics, CURIS, EMD Serono, Genentech, Glenmark, Janssen, Kesios, Lilly, Novartis, Poseida, Teva, Takeda Pharmaceuticals, and Vivolux, and is a consultant for Amgen, Bioclinica, Bristol Myers Squibb, Celgene, CRISPR Therapeutics, Janssen, Karyopharm, Kite Pharma, Legend, Prothena, Servier, Takeda Pharmaceuticals, and SecuraBio. DM is a consultant for and receives honoraria from AbbVie, Celgene, Foundation Medicine, GlaxoSmithKline, Janssen, Legend, Takeda, and Kinevant, and is a member of the Board of Directors or advisory committee and part of the Speaker's Bureau for GlaxoSmithKline, Legend, and Kinevant. SZU is a consultant for AbbVie, Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Sanofi, Seattle Genetics, SkylineDX, and Takeda Pharmaceuticals; receives honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, Pharmacyclics, Sanofi, MundiPharma, and Takeda Pharmaceuticals; receives speaking fees from Amgen, Janssen, and Takeda Pharmaceuticals; and receives research funding from Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda Pharmaceuticals. AJ receives consulting fees and honoraria from AbbVie, Adaptive, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Juno, Karyopharm, and Sanofi, and is a member of the Board of Directors or advisory committee for AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, and Sanofi. ADC reports personal fees from Janssen, Takeda, Bristol Myers Squibb/Celgene, AstraZeneca, Genentech/Roche, Seattle Genetics, Kite Pharma, and Oncopeptides, and personal fees and grants from GlaxoSmithKline and Novartis. AKS receives honoraria from Aventis, Janssen, Amgen, Oncopeptides, Bristol Myers Squibb, GlaxoSmithKline, and Sanofi, and is a member of the Board of Directors or advisory committee for Genomics England and Tempus. PH receives consulting fees and honoraria from AbbVie, Bristol Myers Squibb, Celgene, Janssen, Kite, Sanofi Genzyme, Spectrum, and Takeda Pharmaceuticals; receives research funding from Amgen, Bristol Myers Squibb, Celgene, Sanofi Genzyme, and Spectrum. MH is a current employee of City of Hope Medical Center. AD is a consultant for Novartis and Kite, a Gilead Company. AL receives consulting fees and honoraria from Bristol Myers Squibb, GenMab, Takeda Pharmaceuticals, Janssen, Amgen, and Boehringer Ingelheim; receives research funding from Bristol Myers Squibb, Genentech, Pfizer, Trillium, and Janssen; and receives royalties from patents from Serametrix. IS was an employee of Janssen at the time the study was conducted, and is a current employee of Gilead Sciences. EZ, T-MY, AJA, YO, AB, JDG, JMS, WD, SHZ, and JI are employed by Janssen. CCJ is employed by Janssen, and is a consultant physician at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). DG, XW, and MAk are employed by Legend Biotech. MJC-A was an employee of Legend Biotech at the time the study was conducted, and owns stock in Adaptimmune Therapeutics, Allogene Therapeutics, Atara Biotherapeutics, Bellicum Pharmaceuticals, BioNTech, Bluebird Bio, Cellectis, CRISPR Therapeutics, Editas Medicine, Fate Therapeutics, Iovance Biotherapeutics, Intellia Therapeutics, Juno Therapeutics, Kite Pharma, Legend Biotech, Moderna Therapeutics, NantKwest, Neon Therapeutics, Novartis, AG Pharma, Sana Biotechnology, Sangamo Therapeutics, Sorrento Therapeutics, Tcr2 Therapeutics, Verstem Oncology, and Ziopharm Oncology. FH was an employee of Legend Biotech at the time the study was conducted, and is a current employee of Genentech. SR was an employee of Legend Biotech at the time the study was conducted. FF is employed by Nanjing Legend Biotechnology. YL is a consultant for Bluebird Bio, Celgene, Gamida Cells, Janssen, Huno, Kite, Novartis, Sorrento, Legend BioTech, and Vineti, and receives research funding from Bluebird Bio, Celgene, Janssen, Kite, Merck, and Takeda Pharmaceuticals. TM receives research funding from Janssen. SJ is a consultant for Bristol Myers Squibb, Janssen, Karyopharm Therapeutics, Merck, Sanofi, Legend Biotech, and Takeda Pharmaceuticals. MAg, EO'D, NCM, and DA declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: JNJ-64041757 (JNJ-757) is a live, attenuated, double-deleted Listeria monocytogenes -based immunotherapy expressing human mesothelin. JNJ-757 was evaluated in patients with advanced NSCLC as monotherapy (phase 1) and in combination with nivolumab (phase 1b/2)., Methods: Patients with stage IIIB/IV NSCLC who had received previous therapy were treated with JNJ-757 (1 × 10 8 or 1 × 10 9 colony-forming units [CFUs]) alone (NCT02592967) or JNJ-757 (1 × 10 9 CFU) plus intravenous nivolumab 240 mg (NCT03371381). Study objectives included the assessment of immunogenicity, safety, and efficacy., Results: In the monotherapy study, 18 patients (median age 63.5 y; women 61%) were treated with JNJ-757 (1 × 10 8 or 1 × 10 9 CFU) with a median duration of 1.4 months (range: 0-29). The most common adverse events (AEs) were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours. Peripheral proinflammatory cytokines and lymphocyte activation were induced posttreatment with transient mesothelin-specific T-cell responses in 10 of 13 biomarker-evaluable patients. With monotherapy, four of 18 response-evaluable patients had stable disease of 16 or more weeks, including one patient with a reduction in target lesions. In the combination study, 12 patients were enrolled (median age 63.5 y; women 33%). The most common AEs with combination therapy were pyrexia (67%) and chills (58%); six patients had grade 3 AEs or greater, including two cases of treatment-related fatal pneumonitis. The best overall response for the combination was stable disease in four of nine response-evaluable patients., Conclusions: As monotherapy, JNJ-757 was immunogenic and tolerable, with mild infusion-related fever and chills. The limited efficacy of JNJ-757, alone or with nivolumab, did not warrant further investigation of the combination., (© 2020 The Authors.)

The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2 K660N /p53 mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti-PD-1 alone was ineffective, the erdafitinib and anti-PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRAS G12C -mutant genetically engineered mouse model, which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumor-associated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased T-cell receptor (TCR) clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti-PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti-PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival., (©2019 American Association for Cancer Research.)

Deep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.5%) compared with squamous cell carcinoma (SQCC, 54.4%). The correlation of genomic alterations with immune signatures reveals that low immune infiltration was associated with EGFR mutations in ADC samples, PI3K and/or WNT pathway activation in SQCC. While KRAS mutations are found to be significantly associated with T cell infiltration in ADC samples. The SQCC patients with high antigen presentation machinery and cytotoxic T cell signature scores are found to have a prolonged overall survival time.

Although nonmalignant stromal cells facilitate tumor growth and can occupy up to 90% of a solid tumor mass, better strategies to exploit these cells for improved cancer therapy are needed. Here, we describe a potent MMAE-linked antibody-drug conjugate (ADC) targeting tumor endothelial marker 8 (TEM8, also known as ANTXR1), a highly conserved transmembrane receptor broadly overexpressed on cancer-associated fibroblasts, endothelium, and pericytes. Anti-TEM8 ADC elicited potent anticancer activity through an unexpected killing mechanism we term DAaRTS (drug activation and release through stroma), whereby the tumor microenvironment localizes active drug at the tumor site. Following capture of ADC prodrug from the circulation, tumor-associated stromal cells release active MMAE free drug, killing nearby proliferating tumor cells in a target-independent manner. In preclinical studies, ADC treatment was well tolerated and induced regression and often eradication of multiple solid tumor types, blocked metastatic growth, and prolonged overall survival. By exploiting TEM8+ tumor stroma for targeted drug activation, these studies reveal a drug delivery strategy with potential to augment therapies against multiple cancer types.

Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies., (Published by Elsevier Inc.)