ALLO-316 Demonstrates Early Activity and Safety in Advanced CD70-Positive ccRCC

ALLO-316, an allogeneic CD70-directed CAR T-cell therapy, demonstrated preliminary activity and a manageable safety profile in patients with advanced or metastatic CD70-positive clear cell renal cell carcinoma (ccRCC), according to findings from the phase 1a portion of the phase 1a/1b TRAVERSE trial (NCT04696731) presented at the 2024 SITC Annual Meeting.

Among the 39 patients enrolled, 26 were CD70 positive and evaluable for efficacy outcomes, with the highest responses observed in patients with a tumor proportion score (TPS) of at least 50 (n = 21). Tumor reduction was notably greater in CD70-positive patients with a TPS of at least 50, with 76% of patients (n = 16) achieving tumor burden reductions and 33% of patients (n = 7) experiencing a reduction of greater than 30%.

Dose-limiting toxicities (DLTs) were observed in 2 patients, both of whom received FCA (fludarabine, cyclophosphamide, and alemtuzumab [Lemtrada]) lymphodepletion followed by ALLO-316 at dose level 2 (DL2). These DLTs were autoimmune hepatitis (n = 1) and cardiogenic shock in the setting of multiorgan failure (n = 1).

Treatment-emergent adverse effects (TEAEs) were observed in all 39 patients, with 81% of patients experiencing grade 3 or higher TEAEs. The most common TEAEs included cytokine release syndrome (CRS; any-grade, 62%; grade ≥ 3, 3%), fatigue (59%; 3%), and neutropenia (56%; 51%). No graft-vs-host disease was reported

In the poster, lead study author Samer Srour, MS, MD, and coauthors, explained, “observed responses, including ongoing and deepening responses, in patients with a CD70 TPS [of at least] 50%, [indicate] a single infusion of ALLO-316 could benefit patients with immune checkpoint inhibitor– and TKI-relapsed/refractory RCC.”

Srour is an assistant professor in the Department of Stem Cell Transplantation and Cellular Therapy in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Study Design and Patient Enrollment Criteria

Phase 1a of the trial employed a standard dose-escalation design to primarily evaluate DLTs and the incidence of AEs. Phase 1b primarily focused on identifying the recommended phase 2 dose of ALLO-316, establishing the optimal CD70 TPS cutoff, and assessing the incidence of AEs.

Secondary end points across both phases included assessments of objective response rate (ORR), complete response rate, duration of response, time to response, progression-free survival, CAR expansion kinetics, and CD70 expression on tumor cells.

Patients older than 18 years of age were eligible for enrollment in the TRAVERSE study and were required to have progressive advanced or metastatic ccRCC following prior immune checkpoint inhibitor and VEGF-targeted therapy. Additional enrollment criteria included an ECOG performance status of 0 or 1, adequate organ function, and no untreated central nervous system metastases. CD70 expression was assessed via immunohistochemistry on archival or fresh tumor tissue to confirm eligibility.

Patients received lymphodepletion from days –5 to –3, followed by a single infusion of ALLO-316 on day 0. The trial included comprehensive follow-up to assess safety and efficacy through 60 months.

Baseline Patient Characteristics

The median patient age was 60 years (range, 35-70), and most patients were male (90%). Regarding performance status, 56% of patients had an ECOG PS of 0 or 1. Nearly all patients had stage IV disease (97%), and 82% of patients had undergone prior nephrectomy. The median time since original diagnosis was 43 months (range, 12-216), and the median number of prior therapy lines was 3 (range, 1-8).

All patients had received prior anti–PD-1 therapy, and 1 patient had received anti–PD-L1 therapy. Sixty-four percent of patients had received prior anti–CTLA-4 therapy. All patients had received at least 1 prior TKI, 59% of patients had received at least 2 prior TKIs, and 28% of patients had received at least 3 prior TKIs. Additionally, 79% of patients had been previously treated with cabozantinib (Cabometyx), and 8% of patients had progressive disease despite anti–CTLA-4, anti–PD-1, TKI, and belzutifan (Welireg) therapy.

CD70 positivity was observed in 79% of patients, with 77% of patients having high TPS (≥ 50%) and 23% of patients having low TPS (< 50%). CD70-negative or -unknown status was reported in 21% of patients.

Based on the International Metastatic RCC Database Consortium risk categories, 33% of patients were classified as favorable risk, 51% of patients were classified as intermediate risk, and 10% of patients were classified as poor risk.

The median time from enrollment to lymphodepletion was 5 days (range, 1-10), and the median duration of follow-up was 6.8 months (range, 0.4-36.8).

Among the 39 enrolled patients, 35 received ALLO-316, and 34 were evaluable for disease outcomes. Stratification was based on CD70 expression, with 26 patients identified as CD70 positive. These patients received treatment across 4 dose levels of ALLO-316. At dose level 1 (40 x 10⁶ cells), 3 patients were treated following FCA lymphodepletion. DL2 (80 x 10⁶ cells) included 16 patients, with 5 receiving FCA and 3 receiving FC300 lymphodepletion. Eight patients are planned to receive FC500 lymphodepletion at DL2 in the phase 1b portion of the trial. Dose level 3 (120 x 10⁶ cells) included 6 patients who were evenly split between the FC300 and FC500 lymphodepletion regimens, whereas dose level 4 (240 x 10⁶ cells) included 1 patient treated with FC300 lymphodepletion.

Five patients were CD70 negative, and 3 patients had unknown CD70 expression. These patients received treatment across various dose levels but were not included in the primary efficacy analysis.

Additional Efficacy Outcomes by Dose Level and CD70 Positivity

In the CD70-positive cohort, the best ORR was 27% (n = 7), and responses were exclusively observed in patients with a TPS of at least 50. Confirmed responses were achieved in 24% (n = 5) of these patients.

In the FCA cohort (n = 8), a single confirmed response was observed in 1 patient with a high TPS (13%). In the FC cohort (n = 18), the ORR was 33% (n = 6), with confirmed responses reported in 22% of patients (n = 4).

Patients treated at DL2 with FC500 had an ORR of 38% (n = 3), with confirmed responses in 25% of patients (n = 2). In this cohort, 2 patients (25%) had durable responses lasting beyond 4 months.

Additional Safety Insights

Other common TEAEs included decreased white blood cell (WBC) counts (any-grade, 54%; grade ≥ 3, 49%), anemia (51%; 33%), nausea (51%; 0%), thrombocytopenia (46%; 26%), pyrexia (41%; 5%).

AEs of special interest included infections (any-grade, 62%; grade ≥ 3, 31), including viral infections (33%; 5%); neurotoxicity (44%; 8%), including headache (21%; 0%); and immune effector cell–associated hemophagocytosis-like syndrome (IEC-HS; 13%; 3%). Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 8% of patients, although no grade 3 or higher ICANS was reported.

Investigators outlined recommended IEC-HA management guidance, which included ruxolitinib (Jakafi) and the consideration of dexamethasone with or without anakinra (Kineret) in the frontline setting. If responses were insufficient within 24 to 48 hours, recommended second-line therapy consisted of the addition of dexamethasone with or without anakinra (if not already added in the frontline setting); if no improvement was observed after 24 hours, dosing of ruxolitinib/dexamethasone/anakinra could be escalated. If second-line responses were insufficient within 24 to 48 hours, third-line treatment could consist of emapalumab (Gamifant) or etoposide and/or an “off switch” for adoptive cellular therapy.

Fatal treatment-related AEs included cardiogenic shock (a DLT), sepsis, and failure to thrive in 1 patient 16 months after their last treatment.

TEAEs observed among patients treated at DL2 who received FC500 lymphodepletion (n = 11), were consistent with those seen in the overall population. In this population, the most frequently observed TEAEs were CRS (any-grade, 73%; grade ≥ 3, 0%), fatigue (18%; 0%), neutropenia (64%; 64%), decreased WBC counts (73%; 73%), anemia (64%; 46%), and thrombocytopenia (64%; 27%).

Cellular Kinetic Findings

Vector copy number (VCN) levels were evaluated over time in peripheral blood and tumor biopsy samples. In responders, VCN levels peaked between approximately days 7 and 21 following CAR T-cell infusion and declined gradually beyond day 56. In contrast, nonresponders exhibited lower VCN levels with minimal expansion over the same period. Tumor biopsy samples showed high VCN levels, highlighting the targeted infiltration of ALLO-316 into the tumor microenvironment.

The Dagger effect was characterized by the elimination of CD70-positive host T cells in all evaluable patients by day 10. In contrast, levels of CD70-negative host T cells were generally preserved. This effect was accompanied by robust expansion of ALLO-316 CAR T cells, as evidenced by flow cytometry. By day 56, recovery of CD70-positive host T cells was observed, coinciding with contraction of CAR T cells.

“The CD70 CAR-intrinsic Dagger effect promotes robust expansion and persistence of ALLO-316 with standard FC lymphodepletion, highlighting the potential of Dagger technology as the next-generation allogeneic platform,” the authors concluded. “The phase 1 TRAVERSE study supports further evaluation of ALLO-316 in CD70-positive ccRCC and other CD70-positive malignancies. Enrollment is ongoing at the phase 1b dose regimen of FC500 and 80 x 10⁶ CAR T cells.”

Reference

Srour SA, Chahoud J, Drakaki A, et al. ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC): updated safety and efficacy from the phase 1 TRAVERSE multicenter study. J Immunother Cancer. 2024;12(suppl 2). doi:10.1136/jitc-2024-SITC2024.0322