TRAVERSE Study Shows Preliminary Efficacy and Safety of ALLO-316 in Advanced Clear Cell RCC

Samer A. Srour, MB ChB, MS

The preliminary antitumor activity and encouraging safety profile of the novel anti-CD70 allogeneic CAR T-cell therapy ALLO-316 at low dose levels indicated that the regimen could represent a novel option for heavily pretreated patients with CD70-expressing clear cell renal cell carcinoma (ccRCC). The results may help renew interest in the potential utility of CAR T-cell therapy in the treatment of patients with solid tumors, according to Samer A. Srour, MB ChB, MS.

Initial findings from the dose-escalation portion of the phase 1 TRAVERSE trial (NCT04696731)presented during the 2023 AACR Annual Meeting showed that at a median follow-up of 7.8 months (range, 0.4-18.1), ALLO-316 elicited an overall response rate (ORR) of 17% and a disease control rate (DCR) of 89%in the efficacy-evaluable population (n = 18). Notably, patients with CD70-positive ccRCC (n = 10) achieved an ORR of 30%, a DCR of 100%, and a median progression-free survival of 5 months. Tumor reduction was also positively correlated with a higher baseline tumor CD70 immunohistochemistry H-Score.

Safety signals with the regimen were as expected, and its toxicity profile was similar to that of autologous CAR T-cell products in this setting, Srour said. Based on these results, expansion cohorts are planned to begin by the end of 2023, which may include patients with other CD70-positive tumor types.

“With the data we presented for ALLO-316, there is a new hope that CAR T-cell therapy will work in [patients with] 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. “We are very encouraged by the preliminary efficacy results, [in addition to] the manageable safety profile we have found in this phase 1 dose-escalation study.”

In an interview with OncLive^®, Srour explained the unique construction of ALLO-316, the potential for ALLO-316 to address an unmet need in patients with ccRCC, and how early data from the TRAVERSE study support the continued investigation of ALLO-316 in patients with CD70-expressing tumors.

OncLive: What was the rationale for evaluating the use of ALLO-316 for patients with ccRCC in the TRAVERSE study?

Srour: This is a phase 1 clinical trial exploring the role of ALLO-316, which is an allogeneic CAR T-cell product targeting CD70. This is a first-in-human [trial] for ALLO-316 in solid tumors, specifically kidney cancer. 

CD70 is a tumor antigen expressed in several solid tumors and hematologic malignancies. It’s highly expressed in [approximately] 80% of [patients with] kidney cancer. [Patients with] kidney cancer who have [progressed on] standard therapies have poor prognosis overall. Here, we’re trying to explore this novel agent in these poor-risk populations with kidney cancer. The mechanism of action is targeting the CD70 antigen expressed in [patients with] kidney cancer.

Could you expand on the design of the TRAVERSE trial?

In this phase 1 clinical trial, we used the dose-escalation design of 3+3, which is very well known. We are still in the dose-escalation phase. We have reached dose level 3 of 4 in this clinical trial. We are also exploring 2 different conditioning platforms: one uses fludarabine and cyclophosphamide, and the other one uses fludarabine, cyclophosphamide, and the anti-CD52 monoclonal antibody ALLO-647. That’s the simple study design that we have adopted for this [trial].

What efficacy and safety data for ALLO-316 were shared at the meeting, and how might these findings affect future treatment expectations for patients with advanced solid tumors?

We are very encouraged with the early results from the phase 1 trial presented at [the 2023 AACR Annual Meeting]. We have established that the anti-CD70 ALLO-316 product is relatively safe in this heavily pretreated patient population. [Additionally,] despite [being] a phase 1 clinical trial in dose escalation where we are still [evaluating] the low-dose levels, we have seen very encouraging [efficacy] results. For instance, in patients who have CD70-expressing kidney cancer, the DCR was 100% and the ORR was 30%. These are heavily pretreated patients who historically have poor prognosis.

The biggest highlight from this study, in addition to [the early efficacy], is that we did not see any unexpected safety signals. We have seen very encouraging results for an early-phase study at very low doses. This is a proof of concept that we can do something [with CAR T-cell therapy] for [patients with] solid tumors. There are many challenges with using CAR T-cell therapy [for patients] solid tumors. Most of the studies so far have not shown a clinically meaningful benefit [with other CAR T-cell therapies]. Here, we have shown that we can achieve responses with this novel CD70-directed CAR T-cell product. In the presentation, we had very nice correlatives showing CAR T cells trafficking into the tumor sites in patients who had responses. That [aligns] with our proof of concept that we [could use CAR T-cell therapy] for those poor-risk patients with an unmet need.

The safety profile from this study was not any different from what we see with other approved autologous CAR T-cell products in hematologic malignancies, and most of the [adverse effects] were manageable. Encouraging data from this study [include the agent’s] antitumor activity and ORRs seen at very low doses.

What next steps are planned for the investigation of ALLO-316?

Given these encouraging early results, we will continue to accrue [patients] on this study at multiple centers, and our plan is to finish [testing] the 4 dose levels. I want to emphasize the responses we have seen at the first 2 dose levels [with ALLO-316]. We had treated just 2 [patients] with dose level 3 [at data cutoff], so these results are mostly from dose level 1 and 2. We are hoping to replicate or even improve on these results by accruing more patients at higher-dose levels. From there, hopefully we will take [ALLO-316] to a phase 2 study and expand to [patients with] other CD70-expressing tumors.

How could the unique construction of ALLO-316 allow it to overcome challenges that have limited the safety and efficacy of CAR T-cell therapy in this population?

ALLO-316 has very unique features in the way it was genetically engineered. In addition to knocking out CD52 to allow the anti-CD52 agent ALLO-647 to be used in the conditioning [regimen] to improve the expansion and persistence of the CAR T-cell product, [ALLO-316] also disrupts the TCR gene, which prevents the [development of] graft-vs-host disease. It also has some features to allow masking of CD70 on the CAR construct itself, and by doing that, we prevent fratricide, or self-killing, of the CAR T cell during infusion. We have found a very interesting mechanism in this CAR construct, which we call the dagger effect. By having those features, especially the masking of CD70, ALLO-316 is persistent on its own.

What does this research indicate about the future of ALLO-316 and CAR T-cell therapy in general in patients with advanced solid tumors?

In the context of these very early findings, we want to continue accruing [patients], build on this, and replicate and improve these outcomes. Hopefully, we can carry out [future investigations of ALLO-316] not just [for] patients [with] kidney cancer but [for patients with] other solid tumors and perhaps hematologic malignancies, who [have an] unmet need for a novel product.

Moving forward, we should see more clinical trials [of CAR T-cell therapies for patients with solid tumors], whether they are with ALLO-316 targeting CD70, or other CAR T-cell products to target different solid tumors. We encourage community oncologists to refer patients to be treated with this novel strategy and other researchers to keep [performing] their work in this field to hopefully induce longer, durable remissions and perhaps a cure for solid tumors.

Disclosure: Dr Srour reported receiving honorarium for consulting/speaking for Novartis Pharmaceuticals.

Reference

Srour SA, Kotecha R, Curti B, et al. A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC). Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT011.