New Strategies and Combinations to Improve Outcomes in Immunotherapy in Metastatic Non-Small-Cell Lung Cancer

Immune checkpoint inhibitors have transformed the treatment of metastatic non-small-cell lung cancer, yielding marked improvements in survival and the potential for durable clinical responses. Primary and acquired resistance to current immune checkpoint inhibitors constitute a key challenge despite the remarkable responses observed in a subset of patients. Multiple novel combination immunotherapy and adoptive cell therapy strategies are presently being developed to address treatment resistance. The success of these strategies hinges upon rational clinical trial design as well as careful consideration of the immunologic mechanisms within the variable tumor immune microenvironment (TIME) which underpin resistance to immunotherapy. Further research is needed to facilitate a deeper understanding of these complex mechanisms within the TIME, which may ultimately provide the key to restoring and enhancing an effective anti-tumor immune response. This review aims to provide an introduction to some of the recent and notable combination immunotherapy and cell therapy strategies used in advanced non-small-cell lung cancer (NSCLC), and the rationale for their use based on current understanding of the anti-tumor immune response and mechanisms of resistance within the TIME.

Experience of using 1st line combination immunotherapy in patients with metastatic renal cell carcinoma

The study objective is to evaluate effectiveness and tolerability of 1st line combination immuno-oncological therapy with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma (mRCC) in clinical practice.Materials and methods. The study included 38 patients with mRCC who received combination immunotherapy between July of 2019 and September of 2021. Median follow-up duration was 8 (2-25) months. Mean age of the patients was 58.3 (20-85) years. Previously 22 (57.9 %) patients underwent surgical treatment. Unfavorable physical status 2-3 per the ECOG scale was observed in 10 (26.3 %) patients. Clear-cell type of renal cell carcinoma was diagnosed in 34 (89.6 %) patients, non-clear-cell types in 4 (10.4 %). Sarcomatoid component in the tumor was detected in 8 (21.0 %) patients. G3-4 mRCC variant was verified in 16 (42.1 %) patients. Poor prognosis per the IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) scale was identified in 16 (42.1 %) patients, intermediate -in 20 (52.6 %) patients. All 4 administrations of combination immunotherapy were received by 29 (76.3 %) patients.Results. For median follow-up duration of 8 (2-25) months, 23 (60.5 %) patients continue treatment, 15 (39.5 %) completed therapy with nivolumab and ipilimumab due to various reasons including progression in 11 (28.9 %), death in 2 (5.3 %), intolerable toxicity in 2 (5.3 %) cases. Median duration of combination immunotherapy was 9 (2-24) months. Subsequent antitumor therapy was administered to 3 (7.9 %) patients. During induction course immune-mediated adverse event (grade III-IV hepatitis) developed in 3 (7.9 %) patients. Adverse events were observed in 81.6 % of patients, including grade III-IV in 23.7 % of patients. Objective response was observed in 44.8 % of cases, complete response in 5.3 % of cases, partial response in 39.5 % of cases; controlled disease was achieved in 84.3 % of patients. Median progression-free survival and overall survival were 8 months.Conclusion. In our study despite large number of patients with poor prognosis and poorly differentiated tumors, 64.0 % of patients are alive and 60.5 % of patients continue treatment without disease progression after 18 months of combination immunotherapy. Progression-free survival was significantly affected by sarcomatoid component in the tumor, number of unfavorable factors per the IMDC scale, best response per RECIST 1.1; overall survival was significantly affected by sarcomatoid component in the tumor, sum of measurable lesions, number of unfavorable factors per the IMDC scale, best response per RECIST 1.1, and presence of symptomatic metastases in the brain.

564 Single-cell transcriptomic analysis of immune compartments following combination immunotherapy treatment in poorly immunogenic tumors

BackgroundA major goal in cancer immunology is to rationally design combination therapies that lead to a higher response rate, especially for poorly immunogenic tumors that do not respond to immune checkpoint blockade therapy alone. We previously developed a combination therapeutic strategy, termed AIPV, consisting of a tumor-targeting antibody, a recombinant interleukin-2 with an extended half-life, an anti-PD-1 antibody, and a T cell vaccine [1]. The full AIPV therapy can eradicate large, aggressive, poorly immunogenic tumors in multiple mouse tumor models. However, the exact cellular and molecular pathways involved in such an effective response remain poorly understood.MethodsIn this study, we used single-cell RNA-sequencing to define the detailed cellular and molecular changes in tumors and tumor-draining lymph nodes following the full AIPV therapy or a less effective sub-combination therapy in mice with poorly immunogenic B16F10 tumors.ResultsUsing our approach, we were able to uncover T cells, NK cells, neutrophils, macrophages/monocytes, classical dendritic cells, and plasmacytoid dendritic cells in tumors. We observed profound remodeling of every immune cell type following the effective therapeutic treatment. In particular, we found that classical dendritic cells take up tumor antigens, become activated, and migrate to draining lymph nodes following the AIPV therapy, but not following the less effective IPV therapy. We characterized the transcriptomic changes of these dendritic cells and found that they over-express molecules involved in antigen uptake.ConclusionsOur study comprehensively characterized a system that can overcome resistance to immune checkpoint blockade therapy, paving a cellular and molecular roadmap for immune-based therapeutic strategies that offer clinical benefits for poorly immunogenic tumors.ReferencesMoynihan KD, Opel CF, Szeto GL, Tzeng A, Zhu EF, Engreitz JM, et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat Med. 2016;22: 1402–1410.Ethics ApprovalAll mouse experiments were reviewed and approved by the Koch Institute and Broad Institute Animal Care and Use Committee (IACUC) (ID 0222-08-18).