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Review
. 2024 Mar 19;16(6):1209.
doi: 10.3390/cancers16061209.

Current Treatment Options for Renal Cell Carcinoma: Focus on Cell-Based Immunotherapy

Affiliations
Review

Current Treatment Options for Renal Cell Carcinoma: Focus on Cell-Based Immunotherapy

Angela Hwang et al. Cancers (Basel). .

Abstract

Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space.

Keywords: chimeric antigen receptor (CAR) T-cells; engineered TCR T-cells; immunotherapy; renal cell carcinoma.

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Conflict of interest statement

M.T. has received speaker and consultancy fees from MSD, Angiodynamics and Boston Scientific. The remaining authors declare no relevant conflicts of interest.

Figures

Figure 1
Figure 1
Overview of Treatment Modalities for clear cell RCC (ccRCC). The figure provides a comprehensive overview of the diverse treatment modalities employed for ccRCC. Surgical interventions and radical or partial nephrectomy employ various approaches for direct kidney or tumour removal. Tyrosine kinase inhibitors (TKIs) such as Sunitinib, Pazopanib and Axitinib disrupt critical signalling pathways associated with angiogenesis and cell proliferation. Immunotherapeutic agents, immune checkpoint inhibitors (ICIs) such as Nivolumab and Ipilimumab, enhance the immune response against cancer cells. Additionally, cytokine-induced killer cells (CIKs) and tumour-infiltrating lymphocytes (TILs) involve the selection and in vitro expansion of tumour-reactive cells, infused back into the patient for enhanced cytotoxicity. The emerging field of gene-modified adoptive cell therapies for ccRCC, specifically focusing on Chimeric Antigen Receptor T-Cells (CAR-T) and CAR-NK cells, is highlighted. This includes promising CAR-T therapies targeting CAIX, CD70, AXL, ROR2, and DNAJB8, with ongoing phase I/II clinical trials representing advancements in this area. Additionally, engineered T-cell receptors (TCRs), exemplified by HERV-E-directed TCR-T therapy, are designed to recognize intracellular tumour-associated antigens, presenting a promising avenue for personalized treatment in ccRCC.
Figure 2
Figure 2
Structure of Chimeric Antigen Receptors (CARs) and T-cell Receptors (TCRs). The CAR structure is comprised of an ectodomain, transmembrane (TM) and endodomain region. The ectodomain includes a single-chain fragment variable (scFv) antigen-binding domain derived from the heavy (VH) and light (VL) chains of a monoclonal antibody (mAb), and a hinge/spacer commonly derived from CD8α/CD28/IgG to project the binding domain from the cell membrane provides flexibility in orientation. The transmembrane domain is commonly derived from CD8α/CD28 to anchor the CAR structure to the cell membrane. The endodomain houses an intracellular signalling domain derived from the TCRζ chain (CD3ζ), 1st generation CARs. Later generations incorporated a single T-cell co-stimulatory domain such as 41BB/CD28/ICOS/OX40 fused to CD3ζ to create more efficacious 2nd generation CARs. Later iterations are comprised of 3rd generation CARs that harbour two co-stimulatory domains fused to CD3ζ and 4th generation CARs which incorporate a module to permit transgene production following CAR activation. Additionally, 4th generations CARs (‘Armoured’ CARs) can be designed to induce the production of exogenous cytokines such as IL12/IL15 to augment CAR T-cell function/persistence or overcome a hostile tumour microenvironment (TME). Such transgenes can further include the production of ligands, enzymes, monoclonal antibodies and other immunomodulatory proteins. The structure of the TCR is composed of a αβ heterodimer paired with the invariant dimers CD3εδ, CD3εγ and CD3ζζ. The TCR permits recognition of antigenic peptides presented by major histocompatibility complex (MHC) molecules, and activation signals are propagated through the CD3 dimers.

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