Early Responses With CTX130 Renew Hope for Anti-CD70 CAR T-Cell Therapy in Advanced RCC

Samer A. Srour, MB ChB, MS

Treatment with the anti-CD70 CAR T-cell therapy CTX130 yielded initial antitumor activity with a complete remission (CR) exceeding 3 years, which is the first and longest achieved with an allogeneic product in advanced clear cell renal cell carcinoma (ccRCC), according to Samer A. Srour, MB ChB, MS.¹ He added that these data suggest a potential role for CD70-directed CAR T-cell therapy in the solid tumor space.

Results from the phase 1 COBALT-RCC trial (NCT04438083) of this were presented at the 2024 AACR Annual Meeting and simultaneously published in Cancer Discovery. At the data cutoff date of October 9, 2023, a CR was achieved by 1 patient treated with the first dose level of 3 x 107 CAR T cells at 3 months and lasted for 36 months. Stable disease (SD) was achieved by an additional 75.0% of patients in the overall population (n = 16); 1 patient maintained SD for over 12 months. Overall, the disease control rate (DCR) was 81.3%, the median progression-free survival (PFS) was 2.9 months (95% CI, 1.7-6.0), and the median overall survival (OS) was 20.5 months (95% CI, 14.3-not applicable). The agent demonstrated an acceptable safety profile, and no dose-limiting toxicities were observed across all dose levels.

The data observed with CTX130 provided a foundation for the development of the next-generation anti-CD70 construct, CTX131, which includes 2 additional knockouts for Regnase-1 and TGFβR2 and appears to have improved potency and efficacy vs CTX130 in preclinical models. The safety and activity of this agent will be evaluated in patients with relapsed/refractory solid tumors as part of a phase 1/2 study (NCT05795595).²

“[In this presentation,] we provided proof-of-concept that CAR T-cell therapy is potentially effective in solid tumors,” said Srour, who is an assistant professor in the Department of Stem Cell Transplantation and Cellular Therapy, of the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, in Houston, Texas. “This trial opens the door for us and other investigators to further improve on these outcomes, induce more durable remissions, and potentially cure a subset of these high-risk patients with CAR T-cell therapy.”

In an interview with OncLive^®, Srour explained how the design of CTX130 could overcome some of the challenges of integrating CAR T-cell therapy into solid tumor management, presented early safety and efficacy data from the COBALT-RCC study in CD70-expressing ccRCC, and discussed next steps for the continued investigation of CD70-targeted products in solid tumors.

OncLive: What is unique about the design and mechanism of action of CTX130 compared with other CAR T-cell therapies?

Srour: CTX130 is a first-in-class allogeneic CAR T-cell product. Like any other commercially available CAR T-cell product, [which] are now approved for immunologic malignancies, it has a chimeric antigen receptor construct [for] a special target. CTX130 is targeting CD70, so that’s not unique for this product; what’s unique is that it’s an allogeneic product, so we had to make some additional edits. We did 2 additional edits: one to knock out T-cell receptor α constant [to hopefully] prevent graft-vs-host disease, and one to knock out β2 microglobulin to help the engraftment of the product in the host so they will not reject the product. Additionally, we knocked out CD70 to prevent the self-killing of the CAR T-cell product.

Why does the integration of CAR T-cell therapy into the management of solid tumors continue to be a challenge?

In the solid tumor space, there are several challenges with [ensuring that] CAR T-cell products are effective. The first challenge is identifying the right target, because there’s a lot of targets in the tumor cells and we don’t know which one is the best. We must perform many studies to [figure this out]. The other challenge is overcoming the suppressive tumor microenvironment. Solid tumors are different from liquid tumors in that sense. These are the 2 main challenges that we’ve been working to overcome. We have made several advances over the past few years in overcoming these challenges in solid tumors. In the near future, we’ll hopefully be able to find the [CAR T-cell] product that will be successful, as we’ve done in hematologic malignancies.

What should be known about the eligibility criteria for COBALT-RCC?

This was a phase 1 trial of CTX130 in patients with kidney cancer. The eligibility criteria were similar to any phase 1 clinical trial in regard to the organ [function in] the kidney and liver [as well as ECOG] performance status and other criteria. The only thing unique about this [trial is that] we only included patients with ccRCC, and that these patients had to have prior exposure to [or progression on] standard therapies, [including a] checkpoint inhibitor and TKIs.

What should be known about the safety profile of CTX130, as seen in this study?

The biggest challenges with commercially available CAR T-cell therapies are unique toxicities, [such as] cytokine release syndrome [CRS] and immune effector cell–associated neurotoxicity syndrome [ICANS]. Although rare, there’s also something called hemophagocytic lymphohistiocytosis [HLH], which can be a serious complication. When we use CAR T-cell therapy in solid tumors, we look first into these 3 unique toxicities. Overall, the safety profile [of CTX130] was very encouraging. Our CRS [events] were all grade 1/2, and [occurred in] 50% of the patients. That’s [comparable to] what we can usually see with similar CAR T-cell products. We have not seen any ICANS, which is very encouraging, and we have not seen any cases of HLH. Talking about infections, which also can be a problem for [patients with] hematologic malignancies [treated with] CAR T-cell therapies, we have not seen any grade 3 or higher infections that can be attributed to CTX130. All in all, the safety profile was very encouraging for CTX130 in these high-risk patients.

What efficacy signals were observed with CTX130 in this study, and what are their implications for the use of CAR T-cell therapies in solid tumors going forward?

Selecting the right target and overcoming the suppressive tumor environment have been [some of] the biggest challenges [with CAR T-cell therapy. In our trial], the efficacy was encouraging, [as evidenced by] the DCR exceeding 80% in this high-risk patient population. These are patients who experience some clinical benefit. Either they [achieve] stable disease, [which is when] their cancer has tumor shrinkage but not enough to call it partial response, or they [achieve] CR. The median prior lines of therapy [in this population] was 3, and all [patients had] intermediate- or high-risk disease. What’s more impressive [is] the durable CR that we saw on this trial. One out of 16 patients achieved a CR, and this patient had [progressed on a prior] checkpoint inhibitor and TKI. As we speak, this patient [spent] over 3 years in CR. That’s very encouraging and provides us [with] a proof of concept that CAR T-cell therapy is potentially effective in solid tumors. This [trial] was done in kidney cancer, but we can hopefully [see success in] other solid tumors.

What modifications were made to CTX130 to create the next-generation CTX131 product for further study? How does this CAR T-cell therapy potentially improve upon the original construct?

We were encouraged by the results, but as investigators we always like to see better results. [Although] we saw 1 remission and a DCR over 80%, we asked whether we could make things better. To that point, the CRISPR Therapeutics [team] went back to the lab and screened for several edits that we could potentially make [to CTX130] to improve these outcomes. Although we’re still accruing and treating patients with CTX130, that work was being done. After doing several studies, we found that knocking out the Regnase-1 and TGFβR2 genes can improve the potency and persistence of CAR T cells. [Additionally], TGFβR2 is an important marker in the suppressive tumor microenvironment, so knockout of [this gene] can help CAR T cells infiltrate the tumors. With these 2 additional edits, we now have CTX131, which is the next generation of CTX130. This study [of CTX130] is up and running at The University of Texas MD Anderson Cancer Center and other centers in the United States. So far, we’ve treated a few patients, and hopefully can present some of these data at next year’s [AACR Annual Meeting.]

References

1. Srour SA, Tran B, Haanen JB, et al. CTX130 allogeneic CRISPR-Cas9-engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: long-term follow-up and translational data from the phase 1 COBALT-RCC. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT002.
2. A safety and efficacy study evaluating CTX131 in adult subjects with relapsed or refractory solid tumors. ClinicalTrials.gov. Updated April 2, 2024. Accessed April 7, 2024. ​​https://classic.clinicaltrials.gov/ct2/show/NCT05795595