ALLO-316 Demonstrates Antitumor Activity in Advanced Clear Cell RCC

The allogeneic anti-CD70 CAR T-cell therapy ALLO-316 elicited signals of antitumor activity and showed a tolerable safety profile in patients with advanced or metastatic clear cell renal cell carcinoma (RCC), according to dose-escalation findings from the phase 1 TRAVERSE trial (NCT04696731) presented during the 2023 AACR Annual Meeting.

In efficacy-evaluable patients (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 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, the median progression-free survival was 5.0 months.

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

“With this off-the-shelf CAR T-cell product we have seen encouraging antitumor activity with no unexpected safety signals,” said Srour, who is also an assistant professor in the Department of Stem Cell Transplantation in the Division of Cancer Medicine. “The treatment was initiated with a median of 5 days from enrollment, which is a proof of concept for this off-the-shelf allogeneic product [that] can be given for patients with unmet need [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 due to respiratory failure from COVID-19 infection, which was unrelated to the 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-vs-host disease (GVHD).

There remains a high unmet need for patients with relapsed/refractory RCC, as the population has poor survival outcomes and options are limited following 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 patients with RCC and is detected in other malignances; moreover, its expression is restricted in normal tissue.

TRAVERSE is a first-in-human, dose-escalation, multicenter trial of ALLO-316, which is a novel off-the-shelf, HLA-unmatched, CD70-targeting CAR T-cell treatment. It comprises a TCR and CD52 knockout designed to reduce GVHD risk and facilitate fludarabine/cyclophosphamide conditioning with the anti-CD52 antibody ALLO-647. Additionally, the product has the ability to avoid fratricide, which in turn avoids disruption of CD70 in the CAR cells. ALLO-316 also includes a CD20 mimotope–based intra-CAR off switch which enables effective CAR T elimination with rituximab (Rituxan).

“It has some unique features that might make it more attractive to treat [patients with] kidney cancer,” Srour added.

In the study, investigators 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 cyclophosphamide dosing to 500 mg/m2. Four cell dose levels (DL) of the 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.

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

The primary end points are safety and tolerability, recommended cell dose and conditioning regimen, antitumor activity in patients with varying CD70 expression levels, and kinetics with the 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 female. Most patients (63%) had an ECOG performance status of 0 and 79% had undergone a nephrectomy.

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

The median time from enrollment to the start of conditioning therapy was 5 days (range, 1-15). Ninety-five percent of the 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 male with RCC that metastasized to the lungs; their disease was refractory to nivolumab (Opdivo), pembrolizumab (Keytruda), ipilimumab (Yervoy), and axitinib (Inlyta). Upon receiving 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 male with RCC that metastasized to the adrenal and bone and was refractory to pembrolizumab and axitinib, received the conditioning and CAR T-cell therapies at DL2. Treatment led to stable disease with a 45% decrease in size of the primary left kidney tumor.

The safety data were found to be comparable with what has been reported with autologous CAR T-cell therapies. All-grade and grade 3 or higher treatment-emergent adverse effects 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 higher cytopenia ay day 28 (16%).

Infections were managed with enhanced prophylaxis, Srour said, adding that dose exploration is continuing.

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

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

Expansion cohorts are planned by the end of 2023, with a potential inclusion of additional CD70-positive subtypes, Srour concluded.

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

“CD70 for this disease is a very interesting target, but the target needs to be expressed; otherwise, I don’t think we should expose these patients to this drug. It seems to be safe at least with these dose cohorts, although we have to carefully look at opportunistic infections,” Haanen said. “Clinical benefit was seen, [and] objective responses are seen in refractory patients. We do see expansion and persistence of the cells. I think it’s going to be very interesting to see what happens with higher doses.”

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.