The era of immunotherapy has opened new perspectives in renal-cell carcinoma (RCC), which is one of the tumors most highly infiltrated with CD T-cells and PD-1 expression, partially accounting for its sensitivity to immunotherapy. Other mechanisms to explain its sensitivity include myeloid infiltration, metabolic alterations, loss-of-function mutations, and human endogenous retroviruses.
For this reason, a substantial proportion of patients do not respond to immunotherapies, and those who respond can eventually have disease progression. “It puts us in a time where we need, crucially, to push immune-oncology beyond PD-1, PD-L1, and CTLA-4 inhibitors,” said Toni K. Choueiri, MD, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. “One thing we could do is to start combining therapies,” he added.
Dr Choueiri outlined some of the novel strategies being investigated to overcome the challenges of primary resistance and immune escape in RCC.
One avenue is the use of proinflammatory cytokines. NKTR-214 is a pegylated interleukin (IL)-2 (Peg-IL-2) that is designed to improve the activity and tolerability of IL-2, which at high doses is believed to be a global activator of the immune system. In a phase 1b study with a cohort of 26 patients with advanced RCC, the combination of nivolumab (Opdivo) and Peg-IL-2 led to an overall response rate (ORR) of 46%.
In the entire study of 283 patients with a solid tumor, 14.1% of the patients had grade 3 or 4 adverse events. These preliminary results have led to a phase 3 clinical trial that is accruing patients to compare the combination of nivolumab plus Peg-IL-2 versus sunitinib (Sutent) plus cabozantinib (Cabometyx).
“IL-12 is a cytokine that promotes the activation of natural killer cells, and directs a Th1-oriented immune response,” but its development was fraught with toxicity, Dr Choueiri said. When IL-12 is coupled with NHS76, the cytokine is directed into the tumor microenvironment and the safety profile is superior to that of IL-12 alone. A phase 1b trial of this agent in combination with avelumab (Bavencio) in patients with RCC is ongoing.
Pegilodecakin (Peg-IL-10) at high doses promotes CD8 T-cell expansion and inhibits CD4 T-cells. It induced an ORR of 25% as monotherapy in patients with RCC, which improved to 41% when combined with a PD-1 inhibitor and is associated with few grade 3 or 4 adverse events.
Targeting the Tumor Microenvironment
Reprogramming the tumor immunosuppressive microenvironment is also being attempted, said Dr Choueiri. X4P-001 targets CXCR4. “When you target CXCR4…you’ll prevent the recruitment of T-regulatory cells and myeloid-derived suppressor cells,” he said. “Targeting CXCR4 itself can have a direct antineoplastic effect on tumor cells by inhibiting proliferation.”
In a phase 1 study of 9 patients with RCC who did not have a response to nivolumab alone, after adding the CXCR4 inhibitor, 8 patients had disease control and 1 patient had a partial response.
The recently approved mogamulizumab-kpkc (Poteligeo) is a CCR4-directed monoclonal antibody that is being studied alone and in combination with nivolumab in different solid tumors, and the CSF1R inhibitor cabiralizumab is being developed specifically for RCC, to be used in combination with nivolumab and the anti-CD40 APX005M.
Vaccines and Cell-Based Therapies
NeoVax is an experimental personalized peptide vaccine made from highly predicted HLA-binding tumor neoantigens coupled with a toll-like receptor agonist that is being explored in an upcoming phase 1 clinical trial in patients with fully resected stage III or clear-cell RCC, which represents an unmet need, said Dr Choueiri. The vaccine is being studied in combination with subcutaneous ipilimumab (Yervoy) at one-tenth the intravenous dose in the hopes of increasing T-cell activation.
Novel Immune Checkpoint Inhibitors
Immune checkpoint inhibitors beyond PD-1, PD-L1, and CTLA-4 are being investigated in early clinical trials in patients with advanced RCC and other solid tumors. The immune activator 4-1BB can be targeted by agonists such as the investigational immunotherapy utomilumab, which when used in combination with pembrolizumab (Keytruda) in a phase 1b clinical trial induced an ORR of 40% in patients with RCC.
Eftilagimod is a LAG-3 monoclonal antibody that was shown to have good safety but not clinical activity in a study of 21 patients with RCC. New LAG-3 monoclonal antibodies are in development, including relatlimab (which was initially designed for melanoma) plus LAG525, for RCC.
Tryptophan Pathway Modulators
The tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) pathway has emerged as a potential target to inhibit in combination with PD-1/PD-L1 checkpoint inhibition.
Tryptophan is an amino acid that is involved in the modulation of immune response through the Trp–Kyn–AhR pathway, Dr Choueiri explained. Tryptophan can be metabolized to kynurenines by tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO)1 or 2. Metabolization of tryptophan by IDO and TDO leads to its depletion within T-cells and to increased kynurenine levels that bind the AhR, leading to T-cell anergy and cell-cycle arrest.
IDO1 and PD-1 gene expression correlate strongly across tumor types and serum kynurenine levels increase after PD-1 inhibition and correlate with poorer progression-free survival (PFS).
When combined with pembrolizumab, the selective investigational IDO inhibitor epacadostat had promising clinical activity in patients with RCC in the phase 1 and phase 2 ECHO-202/Keynote-037 study, resulting in an ORR of 47% in patients with none or 1 previous therapy versus 0% in patients with ≥2 previous lines of therapy. The same combination studied in patients with melanoma in ECHO-301 did not improve PFS versus pembrolizumab alone, so the ECHO-302 study that compared epacadostat plus pembrolizumab versus sunitinib or pazopanib (Votrient) in the first-line treatment of RCC was stopped prematurely.
Considering the strong rationale for IDO1 inhibition and the discordant results between early- and late-stage clinical trials with epacadostat, Dr Choueiri postulated that IDO inhibition might have activity in a selected population. To this end, he and his colleagues assessed the kynurenine-to-tryptophan ratio, as an indirect measure of IDO activity, in patients with RCC who received treatment with nivolumab in a phase 3 clinical trial. They found worse probability of survival with an increasing kynurenine-to-tryptophan ratio. “So maybe these are the patients in whom we should add the IDO inhibitor,” he said.
Other IDO1 inhibitors being studied include linrodostat, a potent inhibitor of IDO1, and dual IDO and TDO inhibitors.
Adenosine Pathway Inhibitors
The CD39–CD73–adenosine 2A receptor (A2AR) pathway is a metabolic pathway that is related to the Trp–Kyn–AhR pathway. Adenosine triphosphate is produced by inflammation and tissue injury and is metabolized by CD39 and CD73 into adenosine, which dampens immune response, Dr Choueiri explained. “We know that high CD39 and CD73 expression is associated with poor prognosis,” he added.
The A2AR antagonist CPI-444 has shown single-agent activity, with an ORR of 14%, in patients with RCC but had no additional activity when combined with the PD-L1 inhibitor atezolizumab (Tecentriq).
Other strategies targeting the A2AR pathway include targeting CD39 and CD73, which in addition to inhibiting the adenosine pathway may also inhibit the direct pro-oncogenic effects of these molecules.