Renal cell carcinoma (RCC) is a common cancer with over 400,000 new cases diagnosed globally each year, ranking among the top ten cancers in the United States and United Kingdom. The disease predominantly presents as clear cell RCC (ccRCC), accounting for 75-85% of cases, with papillary, oncocytic, and chromophobe subtypes making up the remainder. Peak incidence occurs between ages 60 and 70, with a 1.5:1 male predominance.
The molecular pathology of RCC is strongly linked to loss of chromosome 3p, where the VHL tumour suppressor gene resides. Biallelic inactivation of VHL is seen in up to 90% of ccRCC cases, leading to upregulation of hypoxia-inducible factor (HIF) proteins and activation of genes like VEGF that promote angiogenesis. Additional tumour suppressor genes on chromosome 3p, including PBRM1, SETD2, BAP1, and TCEB1, also contribute to RCC development.
RCC staging uses the Tumour, Nodes, Metastases (TNM) system, with T1 tumours under 7 cm and T4 tumours invading beyond Gerota's fascia. While surgery is curative for localised disease, up to 30% of patients present with metastatic disease requiring systemic treatment. Risk factors include chronic kidney disease, smoking, obesity, hypertension, and the rare familial von Hippel-Lindau disease.
Clear cell RCC has been demonstrated to be an immunogenic cancer driven by a distinct tumour-specific antigen (TSA) profile. TSAs are uniquely expressed on tumours and elicit immune activation. ccRCC has a high prevalence of insertions and deletions resulting in frameshift mutations that produce tumour-associated neoantigens. Human endogenous retroviruses (ERVs), particularly ERV type E (ERV-E4) which is specific to ccRCC, also generate TSAs and correlate with HIF2A activity.
The ccRCC tumour microenvironment (TME) is heterogeneous and unique, possessing a dense immune cell infiltrate with distinct CD8+ and CD4+ T-cell populations. Paradoxically, increased CD8+ T-cell infiltration has been associated with poorer survival, potentially reflecting a terminally exhausted T-cell phenotype in advanced disease. The myeloid compartment contains immunosuppressive M2-like tumour-associated macrophages and myeloid-derived suppressor cells that correlate with poor prognosis.
Tertiary lymphoid structures in RCC show heterogeneity that can negatively impact dendritic cell maturation and antigen presentation. The complex, heterogeneous cellular environment presents both opportunities and challenges for immunotherapy development, as the immunosuppressive TME must be overcome for effective treatment responses.
For localised disease, surgery remains the only curative treatment, though adjuvant Pembrolizumab showed significant disease-free survival benefit in the KEYNOTE-564 trial. Other adjuvant ICI studies including CheckMate 914 and IMmotion010 did not replicate this benefit. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and PDGFR, such as Sunitinib, Pazopanib, and Cabozantinib, have been the backbone of metastatic RCC treatment since 2006.
Immune checkpoint inhibitors transformed the therapeutic landscape when the CheckMate 025 study showed Nivolumab improved overall survival versus Everolimus in relapsed/refractory patients. The CheckMate 214 trial demonstrated combinatorial Nivolumab and Ipilimumab improved outcomes compared with Sunitinib, establishing ICIs as standard of care. Long-term follow-up showed prolonged overall survival in both intent-to-treat and intermediate/poor risk groups.
Current first-line standard of care includes three ICI-TKI combination strategies: Lenvatinib plus Pembrolizumab (CLEAR trial), Nivolumab plus Cabozantinib (CheckMate 9ER), and Pembrolizumab plus Axitinib (Keynote 426). Despite these advances, treatment outcomes remain lacking with poor overall survival, driving the need for novel approaches such as adoptive cell therapies.
Cytokine-induced killer cells (CIKs) are a heterogeneous group of CD3+CD56+ NK-like cells manufactured from peripheral or cord blood by culturing with IFN-gamma, anti-CD3, and IL2. They have MHC-unrestricted antitumour activity with a diverse TCR repertoire. Early RCC studies showed the CIK arm achieving 53% overall response rate versus 27% for IL-2/IFN-alpha, with improved 3-year PFS and longer median overall survival.
Tumour infiltrating lymphocytes (TILs) are polyclonal, tumour-targeting T-cells expanded from patient tumour biopsies. While TILs have shown strong responses in melanoma with ORR of 49-72%, results in mRCC have been disappointing. An early phase 3 study showed low TIL viability and only 9.9% ORR, and subsequent studies found mRCC TILs lacked cytotoxicity and cytokine secretion compared to melanoma TILs.
Combinatorial approaches pairing CIKs with dendritic cells (DC-CIKs) have shown more promise, with randomised trials demonstrating reduced recurrence and higher 3-year disease-free survival. Adding TKIs and ICIs to DC-CIK therapy, such as Axitinib plus Pembrolizumab-activated DC-CIKs, achieved a 25.6% ORR in treatment-naive or refractory patients. These combination strategies aim to bypass the immunosuppressive TME.
Chimeric Antigen Receptor T-cells (CAR-Ts) are engineered to express a receptor specific to tumour antigens, comprising an ectodomain with a single-chain variable fragment (scFv) for antigen binding, a transmembrane domain, and an endodomain with signalling components. First-generation CARs used only CD3-zeta signalling, while newer generations incorporate co-stimulatory domains like CD28 or 4-1BB, and fourth-generation 'armoured' CARs can produce cytokines like IL-12 or IL-15.
Several promising CAR-T tumour targets have been identified for RCC. Carboxy-anhydrase-IX (CAIX) is commonly overexpressed in hypoxic solid tumours and was among the first investigated targets, though early trials showed significant off-target liver toxicity. CD70, a transmembrane glycoprotein highly expressed in RCC, has emerged as a leading target with the COBALT-RCC study of allogeneic CRISPR-edited CTX130 showing disease control in 69.2% of patients.
At the time of this review, 10 phase I/II CAR-T clinical trials for RCC are recruiting, targeting antigens including CD70, CAIX, ROR2, AXL, DNAJB8, P-MUC1C, c-MET, and HLA-G. Allogeneic approaches using CAR-NK cells, such as the anti-CD70 CAR-NK construct CAT-248 with CRISPR-mediated CD70 knockout, have shown greater than 99% tumour reduction in xenograft models.
The COBALT-RCC phase 1 study tested CTX130, an allogeneic CRISPR-Cas9-edited anti-CD70 CAR-T product, in advanced relapsed/refractory ccRCC patients with a median of three prior treatment lines. Median CD70 expression on tumours was 100%. At 18+ months of follow-up, 1/14 patients had ongoing complete response, 9/14 had stable disease, and the disease control rate was 76.9%. Three of 14 patients experienced serious CRS adverse events.
The TRAVERSE study evaluated ALLO316, an allogeneic TALEN gene-edited anti-CD70 CAR-T, in 17 patients with previously treated advanced or metastatic ccRCC. TCR-alpha knockout reduced graft-versus-host disease risk, and CD52 knockout permitted augmented lymphodepletion. Disease control was achieved in 71% of patients overall, improving to 100% in those with confirmed CD70 expression. Eleven of 17 patients (65%) developed CRS with one grade 3 event.
Additional CAR-T targets under investigation include AXL and ROR2, with a phase I/II study assessing CCT301-59 (ROR2-targeting) and CCT301-38 (AXL-targeting) in relapsed/refractory metastatic RCC. DNAJB8-directed second-generation CAR-T incorporating the B10 binder showed antigen-dependent activation and significant tumour burden reduction in vivo, suggesting cancer stem-like cell antigens may be viable therapeutic targets.
T-cell receptor transduced T-cells (TCR-Ts) recognise intracellular tumour-associated antigens presented by MHC molecules, offering access to a broader antigen repertoire than CAR-Ts which target surface antigens only. TCR-Ts require lower epitope density for activation but are HLA-restricted, limiting therapy to patients with common alleles like HLA-A*02:01. Careful engineering is needed to avoid mispairing of exogenous TCR chains with endogenous ones.
Human endogenous retroviruses (HERVs) are integrated remnants of ancient retroviral infections that are normally silent but aberrantly expressed in certain tumours including ccRCC. The HERV-E derived transcripts CT-RCC-8 and CT-RCC-9 are prevalent in ccRCC but not normal tissues, making them attractive therapeutic targets. Tumour-specific TCR-T products have been developed against HERV-derived proteins.
A first-in-human phase 1 dose escalation trial of HERV-E TCR-T plus IL2 was conducted in 11 metastatic ccRCC patients. Patients tolerated doses up to 5 x 10^7/kg, with toxicities including grade 3-4 febrile neutropenia (57%), capillary leak syndrome (7%), and grade 2 skin rash. The median PFS was short at 62 days, and further data in the RCC TCR-T space is awaited.
Several hurdles remain in developing cell therapies for solid tumours like RCC. A lack of heterogeneously expressed tumour-specific antigens with limited off-target toxicities is a critical problem. CAIX-targeting CAR-Ts demonstrated significant liver toxicity, and CD70 expression on activated immune cells raises fratricide concerns. Multi-antigen targeting and logic-gated CARs using 'AND' and 'AND-NOT' gates are being developed to address these issues.
Maximising T-cell trafficking to solid tumours and overcoming the immunosuppressive TME are secondary challenges. Engineering strategies include expressing chemokine receptors like CXCR1/2/4 to enhance tumour trafficking, targeting cancer-associated stromal cells through fibroblast activation protein (FAP), and armouring T-cells with cytokines such as IL-12 (TRUCKs) or IL-15/IL-7/IL-18 to overcome immunosuppression.
Additional next-generation approaches include dominant negative receptors or switch receptors that convert immunosuppressive TGF-beta signals into T-cell stimulation, gene-editing-based knockout of ICIs like PD-1 on T-cells, and CAR-T-driven secretion of anti-PD-L1 antibodies within the TME. CAR transduced macrophages (CAR-M) are also being explored for their superior tumour homing capabilities and ability to induce phagocytosis.
RCC is an immunogenic cancer, but improving treatment outcomes in the relapsed/refractory setting continues to be challenging. Adoptive cell therapies hold significant promise, yet many products remain in their infancy and are predominantly being tested in preclinical settings. Experimental work has identified multiple potential antigenic targets, but the optimal target antigen remains unknown and therapeutic combinations with TKIs and ICIs need further exploration.
Newer-generation armoured CAR products or combinatory treatments will likely be needed to bypass the hostile tumour microenvironment that limits current cell therapy efficacy. Safety engineering through ON/OFF switches, logic gates, and controlled CAR expression regulated by small molecules or hypoxia-responsive elements within the TME represents promising strategies to manage off-target toxicity.
Ultimately, cell therapies for RCC will require testing in large, randomised controlled trials with appropriate controls to determine how they fit into current treatment paradigms. The identification of improved neoantigens through advanced computational and functional screening pipelines, combined with next-generation cell engineering modules, will be critical for the progress of both CAR and TCR-T therapies in the RCC space.