Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma

Abstract

The management of advanced renal cell carcinoma (RCC) has been transformed by the development of immune checkpoint inhibitors (ICIs), but still most RCC patients do not receive durable clinical benefit. Importantly, RCC differs substantially from other immunotherapyresponsive solid tumors -it has a modest mutation burden, and paradoxically, high CD8 + T cell infiltration has been associated with a worse prognosis. Building on the successes of inhibitory antibodies targeting the PD-1 and CTLA-4 axes, multiple innovative immunotherapies are now in clinical development for the treatment of RCC, including new ICIs, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cellular therapies, and therapeutic vaccinations. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a RCC-specific framework for understanding the necessary immunotherapeutic interventions that underlie an effective anti-tumor immune response. Here, using the structure provided by the well-described cancer-immunity cycle, we outline the key steps required for a successful anti-RCC immune response, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyze encouraging targets within the RCC microenvironment, and review the landscape of antigen-directed therapies in this disease.

Upregulation of ARNTL2 is associated with poor survival and immune infiltration in clear cell renal cell carcinoma

“…Despite significant advances in modalities of diagnosis and treatment in the recent decades, ccRCC is a major threat to health and significantly affects the quality of life of patients worldwide, mainly metastatic patients that benefit few from currently available therapies [ 3 ]. Studies reported that interactions between cancer cells and immune system play a vital role in carcinogenesis of ccRCC [ 4 , 5 ]. Meanwhile, current immunotherapies, such as monoclonal antibodies targeting PD-L1 and/or CTLA4, have become the main therapy for advanced ccRCC treatment [ 6 ].…”

Three-Dimensional Culture Models to Study Innate Anti-Tumor Immune Response: Advantages and Disadvantages

“…The immune system can deeply interact with tumor cells in a hostile TME. While the reactivation of the adaptive immunity by ICB is an additional therapeutic tool against cancer, several solid tumors do not show relevant responses to ICB therapy [ 7 , 8 , 9 , 13 , 77 , 98 , 143 , 160 , 177 ]. NK cells can successfully eliminate tumor cells, but are regulated by a complex balance of positive and negative signals, delivered from the receptor ligands expressed on tumor cells.…”

“…These cytokines can enhance the basal cytolytic activity of NK cells and trigger an evident cytotoxic effect against carcinoma cells [ 172 , 173 , 174 , 175 , 176 ]. The expression of PD1 is limited to a minor population of polyclonal activated NK lymphocytes and mainly in selected donors [ 107 , 177 ]. Thus, the addition of anti-PD1 antibodies to a culture of NK cells with organoids is not needed.…”

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…Building on the success of antibodies targeting PD-1 and CTLA4 immune checkpoints, multiple innovative immunotherapies are currently in clinical development for the treatment of patients with RCC, including ICIs with novel targets, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cell therapies, and therapeutic vaccines to overcome resistance [134][135][136][137]. Although the number of trials targeting these immune modulators is increasing, approval for use of these approaches in the clinic has not been granted, either owing to a lack of clinical benefit or because they are still in the early stages of clinical testing.…”