Allogeneic CAR-T provides tumor control in advanced kidney cancer
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Key findings:
- The investigational CAR T-cell therapy provided 100% disease control for patients with CD70-positive clear cell renal cell carcinoma.
- Research is ongoing to examine efficacy and safety at higher doses.
A single infusion of ALLO-316 provided a high rate of disease control for patients with advanced or metastatic renal cell carcinoma, results from the phase 1 TRAVERSE trial showed.
Treatment conferred particular benefit to patients with CD70-positive clear cell renal cell carcinoma (RCC), findings presented at American Association for Cancer Research Annual Meeting showed.
The agent also exhibited a manageable safety profile, according to researchers.
“We are very encouraged with the preliminary results, particularly for the responses seen at low doses of this novel CAR T-cell product,” Samer A. Srour, MD, assistant professor of medicine in the department of stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center, told Healio. “These initial data provide a proof of concept for the premise that CAR T-cell therapy can be successfully applied to treat solid tumors.”
Background
ALLO-316 (Allogene Therapeutics) is an allogeneic, gene-edited CAR T-cell therapy that targets the protein CD70 on the surface of cancer cells.
The agent — which received fast track designation from the FDA for advanced kidney cancer — is derived from donor induced pluripotent stem cells and uses proprietary transcription activator-like effector nucleases (TALEN) gene editing technology (Cellectis) to disrupt the CD52 gene.
The cell therapy is given in combination with ALLO-647 (Allogene Therapeutics) — an anti-CD52 monoclonal antibody — to provide selective and prolonged lymphodepletion that may delay graft rejection.
The TRAVERSE trial population comprised heavily pretreated patients with advanced or metastatic disease who had a median three prior lines of therapy, including immune checkpoint and tyrosine kinase inhibitors.
Individuals with metastatic clear cell RCC who have experienced disease progression despite previous use of immune checkpoint and tyrosine kinase inhibitors typically have poor outcomes, Srour said. Treatment options for this population are limited, he added.
Approximately 80% of RCC tumors express CD70, with low or no expression on normal tissue, Srour said.
“Additionally, CD70 expression on tumor cells can have an immunosuppressive effect on the tumor microenvironment,” he added. “Hence, it can be an ideal tumor antigen to target.”
Methodology
TRAVERSE is a single-arm, open-label multicenter dose-escalation trial designed to assess the safety and tolerability of ALLO-316 for adults with metastatic clear cell RCC.
All study participants underwent prior treatment with an immune checkpoint inhibitor or VEGF-targeted therapy.
The study enrolled 20 patients with clear cell RCC. Nineteen participants (median age, 62 years; range, 50-70; 84% men) underwent one of two preconditioning therapy regimens prior to a single infusion of ALLO-316 at one of four dose levels, which ranged from 40 × 106 CAR T cells to 240 × 106 CAR T cells.
A target incidence rate of less than 33% for dose-limiting toxicities during the first 28 days after infusion of ALLO-316 served as the study’s primary endpoint.
Other study objectives included evaluation of antitumor efficacy, as well as determining a recommended dosing and preconditioning regimen for future investigation.
Key findings
Median follow-up was 7.8 months (range, 0.4-18.1).
Eleven patients (57.8%) experienced cytokine release syndrome, with one case (5%) of grade 3 or higher CRS reported.
One patient treated at dose level 2 experienced dose-limiting toxicity (grade 3 type 2 autoimmune hepatitis).
Thirteen patients (68%) experienced some form of neurotoxicity, the majority being fatigue and headache; however, no cases of treatment-related immune effector cell-associated neurotoxicity syndrome or graft-versus-host disease occurred during the study.
One patient developed grade 5 respiratory failure related to COVID-19. The death was not attributed to treatment with the study regimen.
The maximum tolerated dose had not yet been reached, investigators noted.
The efficacy analysis comprised 18 eligible patients, including 10 who had CD70-positive clear cell RCC.
Three patients (16.6%) in the study population responded to treatment, with all achieving partial responses. All patients who responded had CD70-positive clear cell RCC.
Researchers reported an 89% disease control rate in the overall study population and a 100% disease control rate among those with CD70-positive clear cell RCC.
Investigators reported median PFS of 5 months for patients with CD70-expressing tumors.
All patients with CD70-positive disease had at least 5% tumor reduction after treatment, with three patients experiencing at least 30% reductions.
Clinical implications
Because CD70 expression is low or absent on normal tissue, investigators expected a low level of on-target, off-tumor toxicities after treatment with this investigational CAR T-cell therapy, Srour said.
“The safety profile was to some extent similar to what we have seen in CD19 autologous CAR T-cell therapies,” he told Healio.
His group also is excited about the preliminary efficacy outcomes, especially given that objective responses and disease control are being observed in CD70-positive clear cell RCC at low dose levels.
“[An] ongoing [study is] now exploring higher dose levels to optimize the recommended phase 2 dose levels,” Srour said. “We are hoping by exploring higher dose levels to confirm and perhaps improve on these efficacy outcomes.”
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Srour SA, et al. Abstract CT011. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
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