Combination Nivolumab, CD137 Agonism, and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma

Abstract

Purpose: Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically PD-1 blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TIL. Patients and Methods: Stage III/IV metastatic melanoma patients with unresectable disease who were anti-PD-1 treatment-naïve were enrolled. TIL were generated in the presence of anti-4-1BB antibody in vitro and expanded for ACT. Patients in Cohort 1 received TIL infusion followed by nivolumab. Patients in Cohort 2 also received nivolumab prior to surgical harvest and during TIL production. Results: A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TIL were successfully expanded from all ACT-treated patients and were tumor-reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36% and median progression-free survival was 5 months. Two non-responders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction. Conclusions: Combination therapy with TIL and nivolumab was safe and feasible for metastatic melanoma patients and provides important insights for future therapeutic developments in ACT with TIL.

Neoantigen-specific CD4+tumor-infiltrating lymphocytes are potent effectors identified within adoptive cell therapy products for metastatic melanoma patients

“…Additionally, infusion of tumor-reactive T cells does not preclude additional therapeutic resistance following ACT, which is an active area of research in our laboratory. 82 Clonal analysis by scRNASeq supported the specificity and function of the discovered neoantigen-specific CD4 + TIL clones. Despite a high degree of inherent similarity in CD4 + TIL likely due to shared ex vivo conditions, the S100A11 Q22R -reactive CD4 + TIL from patient 1 demonstrated a profile marked by relative enrichment of activated and cytotoxic T cells as well as elevated transcripts previously reported as associated with neoantigen specificity.…”

“…Additionally, infusion of tumor-reactive T cells does not preclude additional therapeutic resistance following ACT, which is an active area of research in our laboratory. 82 …”

Decoding the metastatic potential and optimal postoperative adjuvant therapy of melanoma based on metastasis score

“…Unexpectedly, the low MET score group showed a higher response rate to immunotherapy. Considering that PD-1 is the predominant target in melanoma immunotherapy, various PD-1 inhibitors, including nivolumab [ 57 , 58 ], pembrolizumab [ 59 – 61 ], and toripalimab [ 62 , 63 ], have been extensively utilized in clinical settings for MM treatment. PD-1 was chosen for further investigation and analysis.…”

New insights into immune cells in cancer immunotherapy: from epigenetic modification, metabolic modulation to cell communication

“… 234 Researchers reported a phase I clinical trial (NCT02652455) of nivolumab in combination with TIL ACT for the treatment of melanoma which proved to be a safe and feasible treatment. 235 A phase I clinical trial (NCT02421640) of 156 nasopharyngeal carcinoma patients using TILs following concurrent chemoradiotherapy was determined to be safe and objective. 236 This demonstrates the potential survival benefit of TILs in patients with low levels of circulating CD8+ T cells and PDL1 expression.…”