Evolution of cell therapy for renal cell carcinoma

Abstract

Treatment for renal cell carcinoma (RCC) has improved dramatically over the last decade, shifting from high-dose cytokine therapy in combination with surgical resection of tumors to targeted therapy, immunotherapy, and combination therapies. However, curative treatment, particularly for advanced-stage disease, remains rare. Cell therapy as a "living drug" has achieved hematological malignancy cures with a high response rate, and significant research efforts have been made to facilitate its translation to solid tumors. Herein, we overview the cellular therapies for RCC focusing on allogeneic hematopoietic stem cell transplantation, T cell receptor gene-modified T cells, chimeric antigen receptor (CAR) T cells, CAR natural killer (NK) cells, lymphokine-activated killer (LAK) cells, γδ T cells, and dendritic cell vaccination. We have also included perspectives for using other recent approaches, such as CAR macrophages, dendritic cell-cytokine induced killer cells and regulatory CAR-T cells to shed light on preclinical development of cell therapy and advancing cell therapy into clinic to achieve cures for RCC.

Keywords: CAR-NK; CAR-T; Cell therapy; Immunotherapy; Renal cell carcinoma (RCC).

Fig. 1

Hypoxia-inducible factor (HIF) pathway. Under normoxia, von-Hippel-Lindau (VHL) binds to HIF1α, leading to HIF1α degradation. While under hypoxia or in clear cell renal cell carcinoma (ccRCC), the dysfunction of VHL results in HIF1α-HIF1β dimer formation and HIF hyperactivation, resulting in overexpression of many downstream genes involved in angiogenesis, metabolism, and cell-cycle regulation, including carbonic anhydrase IX (CAIX), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Created with BioRender.com

Fig. 2

Cell therapies for renal cell carcinoma. A Allogeneic hematopoietic stem cell transplantation, presenting acute and chronic graft versus host disease (GvHD) with high transplant-related mortality; B Interleukin-2 (IL-2) and IL-2 receptor (IL-2R) variants, where mutants allowing only hIL-2Rβ activation on adoptive T cells but not the hIL-2Rα prevent T cells differentiation into Tregs and induce expansion of effector T cells against the tumor; C T cell receptor gene-modified T cells (TCR-T), which is consisted of a chimeric switch receptor (CSR) combining a ligand-binding domain (e.g., PD-1) with an alternative signaling domain (CD28) able to prevent T cell exhaustion and improve expansion; D Chimeric antigen receptor (CAR) T cells, and E CAR natural killer (NK) cells, both expressing engineered receptors designed against one or more antigens allowing immune cells activation against the tumor; F Lymphokine-activated killer (LAK) cells, that are T and NK cells, mainly expressing NK markers. Despite some efficiency against RCC metastasis, LAK cell therapy has been replaced by more specific cell-based immunotherapies; G γδ T cells, a subset of T cells with non-MHC‐restricted cytotoxic activity. These cells can be engineered for adoptive therapies, and the PD-1/PD-L1 axis does not abrogate their function; H Dendritic cell vaccination, where autologous DCs pulsed with peptides or tumor lysate-derived proteins can stimulate the generation of cytotoxic T cells in cancer patients. Created with BioRender.com

Fig. 3

Immunosuppressive tumor microenvironment (TME). The TME is comprised of tumor cells, stroma, and exhausted immune cells, including dendritic cells (DCs), T cells, NK cells, B cells and macrophages. Created with BioRender.com

Fig. 4

Chimeric antigen receptor (CAR) structure. The CAR consists of an extracellular-hinge region, usually based on a single chain viable fragment (scFv), linked to a transmembrane region and intracellular costimulatory (e.g., 4-1BB, CD28) and stimulatory domains (CD3z). The CAR can be expressed in different immune cells (e.g., T cells, NK cells, Macrophages) and recognize specific tumor antigens independently of the major histocompatibility complex (MHC) presentation. This image summarizes all the molecules that are currently being evaluated as potential targets for CAR in RCC: carbonic anhydrase IX (CAIX), CD70, tyrosine-protein kinase Met (c-Met), mucin-1 (MUC1), receptor orphan tyrosine kinase receptor 2 (ROR2), epidermal growth factor receptor (EGFR). Created with BioRender.com

Fig. 5

Natural killer (NK) cells for adoptive cell therapies. Description of advantages and drawbacks of NK cells used for adoptive cell therapies against RCC, showing the possible sources of these cells. Created with BioRender.com