Commercial CAR T therapy produces activity, tolerability in advanced RCC

ALLO-316, an allogeneic anti-CD70 CAR T-cell therapy, demonstrated antitumor activity and safety in patients with advanced or metastatic clear cell renal cell carcinoma (RCC), according to data from ‘dose escalation of the phase 1 TRAVERSE trial (NCT04696731) presented at the American Association for Cancer Research (AACR) 2023 Annual Meeting.

“With this CAR T-cell product, we have seen encouraging antitumor activity without unexpected safety signals,” according to an expert at the University of Texas MD Anderson Cancer Center.

In patients evaluable for efficacy (n = 18), results showed that at a median follow-up of 7.8 months (range, 0.4-18.1), the objective response rate achieved with ALLO-316 was be 17% and the disease control rate (DCR). ) was 89%. Specifically, in patients with CD70-positive RCC (n = 10), 3 patients (30%) experienced a partial response (PR) with the product and the DCR was 100%. In this subset, median progression-free survival was 5.0 months.

A baseline CD70 tumor immunohistochemistry H score was found to correlate with greater tumor shrinkage, study lead author Samer A. Srour, MB ChB, MS, of the Center explained in a presentation of Cancer at the University of Texas MD Anderson in Houston, Texas. during the meeting.

“With this commercial CAR T-cell product we have seen encouraging antitumor activity without unexpected safety signals,” said Srour, who is also an assistant professor in the Division of Cancer Medicine’s Department of Stem Cell Transplantation. “Treatment was initiated a median of 5 days from enrollment, which is a proof of concept for this available allogeneic product. [that] it can be given to patients with unmet needs [and/or in need of] urgent treatment”.

Regarding safety, 1 dose-limiting toxicity (DLT), grade 3 type 2 autoimmune hepatitis, was reported at the second dose level with conditioning therapy and ALLO-647. There were 2 cases of grade 3 neurotoxicity (syncope and fatigue) and 1 patient died of respiratory failure due to COVID-19 infection, which was unrelated to study treatment.

Cytokine release syndrome (CRS) was found to be manageable and there were no reports of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD).

There is a large unmet need for patients with relapsed/refractory CRC, as the population has poor survival outcomes and limited options after treatment with immunotherapy and TKIs.

CD70 is a promising target for CAR T-cell therapy, Srour explained, as it is expressed in up to 80% of RCC patients and is detected in other malignancies; moreover, its expression is restricted to normal tissue.

TRAVERSE is a first-in-human, multicenter, dose-escalation trial of ALLO-316, a novel HLA-unmatched CAR T-cell treatment targeting CD70. It comprises a TCR and CD52 knockout designed to reduce the risk of GVHD and facilitate fludarabine/cyclophosphamide conditioning with the anti-CD52 antibody ALLO-647. In addition, the product has the ability to prevent fratricide, which in turn prevents disruption of CD70 on CAR cells. ALLO-316 also includes an intra-CAR off switch based on CD20 mimotopes that allows for the effective elimination of CAR T with rituximab (Rituxan).

“It has some unique characteristics that can make it more attractive to deal with [patients with] kidney cancer,” Srour added.

In the study, researchers are exploring 2 conditioning regimens: fludarabine at 30 mg/m² and cyclophosphamide at 300 mg/m², both daily for 3 cycles, with and without ALLO-657 at 10 mg daily for 3 cycles. There was an option to increase the dose of cyclophosphamide to 500 mg/m2². Four cell dose levels (DL) of CAR T-cell therapy were also evaluated: 40 x 106 (DL1), 80 x 106 (DL2), 120 x 106 (DL3), and 240 x 106 (DL4 ). Enrollment in this phase is ongoing.

At enrollment, patients underwent lymphodepletion on day -5, infusion of ALLO-316 on day 0, and a safety and response assessment on day 28. Follow-up continued for 12 months and long-term follow-up for 3 years.

Primary endpoints are safety and tolerability, recommended cell dose and conditioning regimen, antitumor activity in patients with different levels of CD70 expression, and kinetics with different conditioning regimens.

Of the 19 patients included in the safety analysis set presented at the meeting, all had advanced or metastatic (stage IV) clear cell RCC and had received prior treatment with an immune checkpoint inhibitor and TKI. The median age was 62 years (range, 50–70), and 16% of patients were women. Most patients (63%) had an ECOG performance status of 0 and 79% had undergone nephrectomy.

Baseline tumor burden was at least 50 mm in 79% of patients and at least 100 mm in 42% of patients. The median time since original diagnosis was 42.7 months (range, 12.1–216.3), and the median number of prior lines of therapy received was 3 (range, 1–8). A total of 73.7% of patients had more than 1 checkpoint inhibitor failure and 52.6% had more than 1 TKI failure.

The median time from enrollment to initiation of conditioning therapy was 5 days (range, 1-15). Ninety-five percent of enrolled patients received ALLO-0316 at DL1 (n = 9), DL2 (n = 8), and DL3 (n = 2).

Srour also discussed an individual patient case of a 68-year-old man with RCC that metastasized to the lungs; his disease was refractory to nivolumab (Opdivo), pembrolizumab (Keytruda), ipilimumab (Yervoy), and axitinib (Inlyta). On treatment with the conditioning regimen and ALLO-316 at DL1, the patient had an initial PR at 1 month that continued to deepen until 8 months.

A second patient, a 70-year-old man with RCC who metastasized to the adrenal gland and bone and was refractory to pembrolizumab and axitinib, received conditioning and CAR T-cell therapies at DL2. Treatment resulted in stable disease with a 45% decrease in the size of the primary tumor in the left kidney.

Safety data were found to be comparable to those reported with autologous CAR T-cell therapies. Treatment-emergent adverse events of all grade and grade 3 or higher included infusion-related reactions (5% and 0%, respectively), CRS (58% and 5%), neurotoxicity (68% and 11%), infection (42% and 21%), and prolonged grade 3 or greater cytopenia on day 28 (16%).

The infections were managed with improved prophylaxis, Srour said, adding that dose exploration is ongoing.

Pharmacokinetic data showed that a large expansion of CAR T cells was observed following both conditioning regimens and at relatively low doses. The mean peak expansion was 35,000 copies/µg in peripheral blood. In addition, high VCN was reported in 3 of 4 available tumor aspirates. This highlights ALLO-316’s ability to infiltrate the tumor environment, Srour noted.

Furthermore, the results showed that ALLO-316 eliminates CD70-positive host T cells, which in turn prevents allorejection and supports persistence.

Expansion cohorts are planned for late 2023, with possible inclusion of additional CD70-positive subtypes, Srour concluded.

John Haanen, MD, PhD, group leader at the Netherlands Cancer Institute in Amsterdam, Leiden University Medical Center in Leiden, and Center Hospitalier Universitaire Vaudois de Laussane, all in the Netherlands, commented on these data after Srour’s presentation.

“CD70 for this disease is a very interesting target, but it needs to be expressed; otherwise, I don’t think we should be exposing these patients to this drug. It appears to be safe at least with these dose cohorts, although we need to look closely at opportunistic infections,” Haanen said. “A clinical benefit was seen, [and] Objective responses are seen in refractory patients. We see the expansion and persistence of cells. I think it will be very interesting to see what happens at higher doses.”

reference

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