Garg, I. D.

Background: Approximately 30% of renal cell carcinoma (RCC) cases present with de novo metastatic disease, while 20% to 30% of those with localized disease will develop metastases following surgical resection. Various drug classes have been investigated to treat RCC, including cytokine-based therapies, small molecule Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitors (TKIs) and antibody-based therapies. Up to 58% of patients fail to respond to primary immune checkpoint inhibitor (ICI) therapy, and nearly all initial responders experience disease progression due to the development of secondary resistance. Consequently, novel treatment options are being investigated. Objective: Review the rapidly evolving ADC therapeutic landscape in metastatic RCC including recent trials, emerging ADCs targets, and future directions for ADCs in the treatment of advanced RCC. Methods: Literature review using the MEDLINE database on important trials and presentations from the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO) conferences. Key words used included “renal cell carcinoma,” “RCC,” “metastatic RCC,” “advanced RCC,” “antibody-based therapies,” “immunotherapy,” “clinical trials,” and “emerging drugs.” Specifically for review of ADCs in RCC, the following search string was used with additional review of bibliographies from retrieved papers: “((antibody drug conjugate) OR (antibody-dependent cellular cytotoxicity) OR (chimeric antigen receptor)) AND ((kidney cancer) OR (renal cell carcinoma))”. Results: Several promising targets including MMP14, EGFR, MCT4, CA9, MET, CDH13, B7-H3, and PSMA were identified with relevant preclinical and clinical studies reviewed. Conclusions: While ADCs therapeutics have not shown benefit to date for renal cell carcinoma, there are ample promising candidates and targets for future research.

AbstractRenal cell carcinoma (RCC) is among the top 10 most common cancers in both men and women with an estimated 75 000 cases each year in the US. Over the last decade, the therapeutic landscape for patients with metastatic RCC has significantly evolved, with immunotherapy emerging as the new front-line therapy. Despite significant improvement in toxicity profile and survival outcomes, key concerns such as patient selection, treatment sequencing, and intrinsic and acquired resistance remain unresolved. Emerging options such as antibody-based therapeutics (eg, anti-CD70, anti-CA9, and anti-ENPP3) are being explored in clinical trials for patients with cancer resistant or refractory to current immunotherapies. Despite positive results for hematological cancers, breast cancer, and more recently bladder cancer, most antibody-based therapies failed to improve the outcomes in patients with advanced RCC. This underscores the need to understand the underlying causes of failed responses to this treatment class, which will ultimately support the rational design of more effective and tolerable treatments. In this review, we summarize the evolving landscape of RCC therapeutics and describe recent clinical trials with emerging antibody-based therapeutics. We also describe the challenges that need to be overcome for the successful creation of therapeutic antibodies for treating RCC.

Abstract T cell–mediated cancer immunotherapies, including anti–PD-1 and CAR-T cells, are becoming standard treatments for many cancer types. One potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. We recently reported results from an innovative, genome-wide screen to identify endogenous T cell genes that enhance intratumoral accumulation using the Sleeping Beauty (SB) transposon system. We successfully identified many promising candidates with this in vivo approach using immunocompetent models of solid tumors. Others have performed similar independent whole-genome and targeted screens in T cells assessing tissue localization using adoptive T cell transfer approaches. To determine how our gene candidates compared with significant candidates identified in these independent screens, we performed a formal rank aggregation to generate a single, integrated ranked list in descending order of selection strength. Aggregated results yielded approximately 1500 T cell gene candidates whose biological functions are enriched in chemotaxis. We hypothesized that these candidates represent novel therapeutic targets to improve T cell migration into solid tumors. Here, we present in vivo validation of two of the most strongly selected candidates, including AP2-associated protein kinase 1 (Aak1) and Small Proline-Rich Protein 1B (SPRR1B). Importantly, in vivo migration of adoptively transferred T cells into tumors was significantly increased when the T cells overexpressed AAK1DN125 or SPRR1B. Our observations strongly support the strength of genomic screens to identify truly novel candidates for further development as immunotherapies to enhance T cell homing to the tumor microenvironment. Supported by Mayo Clinic Graduate School of Biomedical Sciences, K22 (K22CA225786, PI: LM Rogers), and Cancer Immunology and Immunotherapy Program Pilot Award (PI: LM Rogers)