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Background: Phase 1/2 dose-escalation and expansion study evaluating varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors., Methods: Phase 1 evaluated the safety of varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures., Results: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%)., Conclusion: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes., Trial Registration Number: NCT02335918., Competing Interests: Competing interests: RES: none. MP: none. MC: reports grants from Bristol Myers Squibb for projects outside this manuscript, personal fees from Merck, InCyte, Moderna, ImmunoCore, and AstraZeneca. Additionally, she has an immediate family member who is employed at Bristol Myers Squibb and receives unvested stock as a form of compensation. AW: none. BS: none. OR: research support from Merck. Speaker for activities supported by educational grants from BMS and Merck. Consultant for Merck, Celgene, Five Prime, GSK, Bayer, Roche/Genentech, Puretech, Imvax, Sobi. In addition, Dr Rahma has patent ‘Methods of using pembrolizumab and trebananib’ pending. DCC: consultant for Nektar, Werewolf, Pfizer, and HUYA. NR: was an employee of Herbert Irving Comprehensive Cancer Center, Columbia University, NY, USA when the analysis was conducted and is a stockholder of Gritstone bio and Synthekine and is a current employee of Synthekine. MZ: consulting fees from Alkermes, PIO Therapeutics, Iovance, Biontech DSMC, Regeneron, Merck, Kadmon-Sanofi, Incyte, Dragonfly, Evoveimmune, Rootpath, Anaptys, Numab, Biond, Adaptimmune, Bristol-Myers, Simcha, Verastem, Pfizer, Innate Pharma, Pierre-Fabre, Nextcure, Alligator, Ocellaris-Lilly, Immunoscore, Glaxo Smith Kline, Adagene, Asher, Kanaph, iTEOS, Genocea, Trillium, Sapience, Targovax, Molecular Partners, Ontario Institute for Cancer Research, Jazz Pharmaceuticals, Gilead, Tessa, Stcube, Oncosec, Astra Zeneca, Agenus, Idera, Apexigen, Rubius, Genetech-Roche, Boston Pharmaceuticals, and Servier. Stock or stock options for Adaptive Biotechnologies, Amphivena, Intensity, Actym, Nanobot, Johnson and Johnson, Glaxo-Smith Kline, Evolveimmune, Nextcure, Torque Repertoire, Oncohost, Rootpath, and Asher. JL: none. JEB: grants to the University of Arizone for cancer-related clinical research from Astra Zeneca, Aveo, Celldex, CUE, Lilly, and Novartis. RB: none. AS: BMS speaker bureau. AJ: reports no relevant conflicts. AJ owns stock/options on Champions Oncology and Suvica. AJ institution has contracts for trials where AJ is local PI with Pfizer, Merck, SQZ, Moderna, Iovance, Khar Biopharma, DebioPharm, Cantargia and Sanofi. DR: Research support (paid to DFCI): Acerta Phamaceuticals; Agenus; Bristol-Myers Squibb; Celldex; EMD Serono; Enterome; Epitopoietic Research Coorporatioin; Incyte; Inovio; Insightec; Novartis; Omniox; Tragara. Advisory/consultation (paid to Dr Reardon): Abbvie; Advantagene; Agenus; Agios; Amgen; AnHeart Therapeutics; Avita Biomedical, Inc., Bayer; Boston Biomedical; Boehringer Ingelheim; Bristol-Myers Squibb; Celldex; Deciphera; Del Mar Pharma; DNAtrix; Ellipses Pharma; EMD Serono; Genenta; Genentech/Roche; Hoffman-LaRoche, Ltd; Imvax; Inovio; Kintara; Kiyatec; Medicenna Biopharma, Inc.; Merck; Merck KGaA; Monteris; Neuvogen; Novartis; Novocure; Oncorus; Oxigene; Regeneron; Stemline; Sumitono Dainippon Pharma; Pyramid; Taiho Oncology, Inc.; Vivacitas Oncology, Inc., Y-mabs Therapeutics. ThK: none. FI: consulting or Advisory Role: Novocure, Regeneron, Abbvie, Merck, Tocagen, Alexion, Guidepoint Global, Gennao Bio, Xcures, Innovation Spec, Medtronic, MassiveBio, Kiyatec, MimiVax. Speakers’ Bureau: Prime Oncology; Institutional Research Funding: Merck, Bristol-Myers Squibb, Tocagen, FORMA Therapeutics, Celldex, Northwest Biotherapeutics, Sapience Therapeutics, Novocure. Travel, Accommodations, Expenses: Oncoeutics. DSS: employee of AstraZeneca and have stock options with the same. JBA: Honoraria from Bristol Myers Squibb, Pfizer/EMD Serono, and Astellas/Seattle Genetics. Meeting and travel support from EMD Serono and Bristal Myers Squibb. Participation on a Data Safety Monitoring Board or Advisory Board for Pfizer, Merck, EMD Serono, Astellas, Seattle Genetics, Immunomedics, AZD, Aveo, Exelixis, Janssen, Pfizer/Myovant. TRH: employee of Celldex and own Celldex stock. TR: was an employee of Celldex at the time the study was conducted. MY: employee of Celldex and owns Celldex stock. TiK: employee of Celldex and owns Celldex stock., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP)., Methods: Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3 H-thymidine incorporation, and ELISA., Results: Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3-2.6-fold increases in CD4+T, CD8+T, and CD56 bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group., Conclusions: Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56 bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses., Competing Interests: Competing interests: MM and AG are employees of RevImmune who provided CYT107 for this trial. LF, RKP and PM served in advisory/consulting roles for Dendreon. EYY has received grant funding from Dendreon., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)