Allogene’s CAR-T ALLO-316 Demonstrates Ability to Produce Responses in Renal Cell Carcinoma, but Safety Data Includes 3 On-Study Deaths

Allogene Therapeutics’ ALLO-316, an allogeneic CD70-directed chimeric antigen receptor T-cell (CAR-T) therapy, has produced responses in patients with advanced or metastatic renal cell carcinoma (RCC) treated in the phase 1 TRAVERSE clinical trial (NCT04696731); notably, however, 3 on-study patient deaths were reported.¹ The data were presented at the Society for Immunotherapy of Cancer’s (SITC) 39th Annual Meeting, held November 6-10, 2024, in Houston, Texas.

The study’s efficacy findings covered 26 patients who had confirmed CD70-positive RCC and were evaluable as of the October 14, 2024 data cutoff. Among 8 patients who were treated at dose-level 2 (80 million CAR T-cells) after a standard FC500 [fludarabine (30 mg/m2/day) and cyclophosphamide (500 mg/m2/d) for 3 days] lymphodepletion regimen, which was used as the dose for the phase 1b expansion cohort, the best overall response rate (ORR) was 38% (3/8). For patients in the group with a high CD70 Tumor Proportion Score (TPS), which was defined as a TPS of 50% or greater, the best ORR was 50% (3/6). Furthermore, the confirmed ORR, which unlike the best ORR required confirmation of a complete response or partial response at the subsequent visit, was 25% (2/8) for the group of 8 patients. For the 6 patients with a high CD70 TPS, the confirmed ORR was 33% (2/6). For the whole group of 26 evaluable patients, the best ORR was 27% (7/26), the best ORR in patients with a high CD70 TPS was 33% (7/21), the confirmed ORR was 19% (5/26), and the confirmed ORR in patients with a high CD70 TPS was 24% (5/21). Allogene pointed out that 16 of 21 patients (76%) who had a high CD70 TPS showed a decrease in tumor burden and that 2 of 6 patients (33%) with a high CD70 TPS who were treated with the phase 1b expansion regimen achieved durable responses that remained ongoing at 4 months posttreatment or later.

“ALLO-316, the leading ‘off-the-shelf' CAR-T product candidate currently in development for solid tumors, continues to show remarkable potency in the TRAVERSE trial,” Zachary Roberts, MD, PhD, EVP, research and development and chief medical officer of Allogene, said in a statement.¹ “Data from the phase 1 study demonstrating significant antitumor activity in patients with metastatic disease resistant to multiple therapeutic classes, even with standard lymphodepletion, potentially marks a major advancement in the field. The unprecedented cell expansion and persistence driven by CD70 CAR-intrinsic Dagger technology, along with strong evidence of tumor infiltration by CAR T-cells, highlights the distinctive features of ALLO-316. We believe these findings from our phase 1 trial lay the groundwork for a new generation of allogeneic cell therapies.”

The safety data set for the trial included 39 patients who were treated with ALLO-316, including some who were not included in the efficacy analysis. The most common adverse events (AEs) in the safety set constituted cytokine release syndrome (CRS) (62% of patients), fatigue (59%), neutropenia (56%), decreased white blood cell count (54%), anemia (51%), and nausea (51%). Allogene pointed out that only 1 patient (3%) experienced a case of CRS that was graded as 3 or higher in severity, that only 3 patients (8%) experienced cases of immune effector cell-associated neurotoxicity syndrome, and that no cases of graft versus host disease were reported. Infections occurred in 24 patients (62%), with 12 patients (31%) experiencing infections that were grade 3 or higher. Neurotoxicity occurred in 17 patients (44%), with 12 patients (31%) experiencing neurotoxicity AEs that were grade 3 or higher. Immune effector cell (IEC) associated HLH-like syndrome (IEC-HS) occurred in 5 patients (13%), with 1 patient (3%) experiencing a case of grade 3 or higher.

Notably, 3 patients died on-study. One patient died from cardiogenic shock, which was considered 1 of 2 dose-limiting toxicity events that occurred in patients in the trial. Another patient died of sepsis from multidrug resistant Klebsiella pneumoniae. Allogene stated that this patient had previously experienced a case of muscle abscess and bacteremia from the same multidrug resistant Klebsiella and was receiving anakinra and dexamethasone for hyperinflammation. A third patient’s death was attributed to “failure to thrive.” The patient, who died 16 months after receiving ALLO-316, had shown a response of stable disease at 12 months posttreatment, but had no further interval scans to assess the status of their disease.

ALLO-316 is not the only CAR-T therapy currently in development for RCC. On June 21, 2023, Invectys initiated a phase 1/2a clinical trial (NCT05672459) for its CAR-T therapy IVS-3001 in patients with HLA-G-positive clear cell RCC, HLA-G-positive epithelial ovarian carcinoma, and other types of HLA-G-positive solid tumors.² IVS-3001 targets HLA-G, a checkpoint molecule that under normal conditions is only expressed during pregnancy to protect the fetus from an immune response but is also expressed by some cancers.

“This is a great step towards bringing new solutions to patients,” Julien Caumartin, PhD, the chief scientific officer of Invectys, said in a July 2023 statement.¹ “There are currently far too few reliable solutions on the market for solid tumor cancer patients, due to the complexity of solid tumors. Our vision is to provide broad-ranging solutions to the patients, and we are eager to carry our CAR-T cells to the clinic and challenge the paradigm of CAR-Ts in solid tumors.”

REFERENCES
1. Allogene Therapeutics announces positive phase 1 data demonstrating the potential of ALLO-316 in heavily pretreated patients with advanced renal cell carcinoma at SITC and IKCS. News release. Allogene Therapeutics, Inc. November 7, 2024. Accessed November 15, 2024. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-announces-positive-phase-1-data
2. Invectys announces initiation of phase 1/2a clinical trial in solid tumors and change in leadership. News release. Invectys, Inc. July 13, 2023. Accessed July 18, 2023. https://www.invectys.com/news/invectys-announces-initiation-of-phase-1-2a-clinical-trial-in-solid-tumors-and-change-in-leadership/