Off-the-shelf CAR-T produces complete remission in patient with advanced kidney cancer
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Treatment with CTX130, a novel chimeric antigen receptor T-cell therapy, led to disease control in more than three quarters of patients with advanced clear cell renal cell carcinoma, results from a phase 1 trial showed.
Data from the COBALT-RCC study presented at Society for Immunotherapy of Cancer Annual Meeting also revealed one patient with stage IV disease experienced complete remission lasting more than 2 years after a single infusion of the investigational agent, researchers noted.
Background
CTX130 (CRISPR Therapeutics) is an allogeneic, CRISPR/Cas9 gene-edited CAR T-cell therapy that targets CD70, an antigen known to be expressed by certain solid tumors and hematologic malignancies.
Kidney cancer is one of the most common cancer types, with about 50,000 patients diagnosed in the U.S. annually, according to Sumanta K. Pal, MD, co-director of City of Hope's kidney cancer program and a HemOnc Today Editorial Board Member.
Clear cell is the most common subtype among patients with renal cell carcinoma — comprising approximately 70% to 80% of cases — and tends to respond poorly to currently available therapies, he added.
“Ultimately, up to 30% of patients will develop metastases, and this will require systemic therapy,” Pal said during a presentation. “Our study is predicated on the fact that renal cell carcinoma, especially clear cell disease, appears to have relatively high and consistent expression of CD70.”
Methodology
The multicenter phase 1 COBALT-RCC trial enrolled 14 adults (median age, 64.5 years; range, 54-77) with stage IV relapsed or refractory unresectable or metastatic clear cell renal cell carcinoma to evaluate the safety and efficacy of CTX130. The study included heavily pretreated patients with previous exposure to both immune checkpoint and tyrosine kinase inhibitors.
Patients received standard lymphodepleting chemotherapy followed by a single infusion of CTX130 at one of four dose levels, ranging from 3 × 107 to 9 × 108 CAR T cells.
Safety and dose-limiting toxicity served as the primary endpoints for the dose-escalation portion of the study, with a data cutoff point of May 2, 2022. Objective response rate served as the primary endpoint for the dose-expansion portion of the study.
Key findings
A single infusion of CTX130 conferred a disease control rate of 76.9% among the 14 patients who received the investigational therapy.
Investigators reported stable disease in nine patients (69.2%) that lasted at least 4 months in four patients (30.8%).
One patient (7.7%) experienced a durable complete remission that is ongoing as of their 24-month follow-up, Pal confirmed during the presentation.
Researchers found that CAR T-cell expansion occurred across all four dose levels evaluated, with a developing association between higher dose level and disease control.
Investigators reported no dose-limiting toxicities during the study.
Seven patients (50%) experienced grade 1 or grade 2 cytokine release syndrome, with no cases of grade 3 or higher CRS reported during the study.
Three patients developed serious infections unrelated to treatment with CTX130, including one patient death (grade 5 pneumonia with grade 4 dyspnea).
Further safety analysis showed no occurrence of immune effector cell-associated neurotoxicity syndrome, graft-versus-host disease or hemophagocytic lymphohistiocytosis.
Clinical implications
The results of this first-in-human trial of a CD70-targeted CAR T cell therapy in clear cell renal cell carcinoma showed an acceptable safety profile with indicators of efficacy, Pal noted.
“This is encouraging initial antitumor activity and, to our knowledge, represents the first durable complete response to an allogeneic CAR T-cell therapy in a patient with a relapsed or refractory solid tumor,” Pal said.
His group is already working on a second-generation version of the agent that is currently in preclinical testing.
“We are looking to move forward with CTX131, which incorporates additional [gene] edits that we hope will increase the potency of this cell therapy,” he told Healio.
Perspective
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Bingfei Yu, PhD
Allogeneic CAR T-cell therapy provides many advantages in manufacturing, cost and T-cell quality, potentially making it accessible to more patients. However, the safety and efficacy of these “off-the-shelf” CAR-T cells are largely unknown, specifically in solid tumors. Thus, results from the phase 1 COBALT-RCC study are very timely and essential.
The safety profile from this study is excellent, with manageable adverse events. No graft-versus-host disease indicates effective mitigation of immune rejection by beta-2 microglobulin (B2M) knockout (KO), allowing this off-the-shelf CAR-T to benefit more patients without human leukocyte antigen matching. This result also suggests that natural killer cell rejection on B2M KO is minimal. Such a great safety profile increases the possibility of further increasing the dose and repeat dosing.
One concern about the CRISPR-edited T-cell product is the chromosome abnormality induced by CRISPR-Cas9 cutting, especially on multiple genes. It requires cautious screening of chromosome aneuploidy on the pre-infusion T cells and follow-up after infusion.
For efficacy, it is very encouraging to see a 76.9% disease control rate, although in a small cohort, and one patient with complete remission at more than 24 months. Follow-up of clinical efficacy is necessary, especially in monitoring the durability of allogenic CAR-T, the infiltration of these cells in solid tumors and antigen loss that might be induced by CAR-T trogocytosis.
Perspective
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Gabriel Abril Rodriguez, PhD
It is exciting to finally have the first results from this phase 1 dose-escalation study of CTX130, a CD70-targeting allogeneic CAR T-cell therapy, which shows an encouraging disease control rate with no unexpected on-target, off-tumor toxicity.
This clinical trial tests several critical points that are of high interest for the future of immuno-oncology cell therapies, including the:
- safety profile of allogeneic T cells that could be rapidly used off the shelf;
- use of CRISPR/Cas9-engineered CAR T cells to eliminate the donor’s T cell receptor and prevent graft-versus-host disease, as well as to increase the persistence of the infusion by deleting major histocompatibility complex class I expression; and
- clinical antitumor potential of CD70 as a CAR-T target for solid tumors with high CD70 expression.
Although the study had promising results, it is still too early to make any strong conclusions. There are critical parameters to further investigate, such as the persistence of the CAR T-cell infusion product, as well as potential clinical relapses due to loss of target antigen. In addition, we cannot exclude that, although CTX130 is generally well-tolerated, three of the 14 patients experienced serious episodes of CRS.
This clinical trial seems to be the first one of many more to come in which the antitumor activity of CD70-targeting CAR T cells in solid tumors is tested. For example, I will be on the lookout for the first results of the TRAVERSE trial, testing Allogene’s CD70 allogeneic CAR-T product, ALLO-316.
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Pal S, et al. Abstract 558. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 8-12, 2022; Boston.
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