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Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities.

ABSTRACT: Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

SUBMITTER: Zarrabi K

PROVIDER: S-EPMC8344970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as "immune checkpoints") including PD-1/PD-L1 has led to impressive tumor regressions in several cancers. Preclinical studies suggest that these immune checkpoints may also play a role in regulating tumor immunity in MM. Indeed, myeloma was among the first tumors wherein therapeutic efficacy of blockade of PD-1 axis was demonstrated in preclinical models. Expression of PD-L1 on tumor and immune cells also correlates with the risk of malignant transformation. However, early clinical studies of single agent PD-1 blockade have not led to meaningful tumor regressions. Immune modulatory drugs (IMiDs) are now the mainstay of most MM therapies. Interestingly, the mechanism of immune activation by IMiDs also involves release of inhibitory checkpoints, such as Ikaros-mediated suppression of IL-2. Combination of PD-1 targeted agents with IMiDs led to promising clinical activity, including objective responses in some patients refractory to IMiD therapy. However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM.

Dataset Information

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities.

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