Tumor Response in Allogene Trial Offset by Fatal Adverse Events

15 November 2024
Allogene Therapeutics has recently presented a blend of promising and concerning results for its leading solid tumor CAR-T therapy, ALLO-316. This off-the-shelf CAR-T candidate, designed to target the CD70 antigen, was showcased in a Phase I trial targeting patients with advanced or metastatic renal cell carcinoma (RCC). Despite the encouraging anti-cancer activity observed, the therapy was also linked to three patient deaths.

The TRAVERSE study, which is assessing ALLO-316, was highlighted at the annual meeting of The Society for Immunotherapy of Cancer (SITC). The study enrolled 26 evaluable patients to determine efficacy outcomes. Among these patients, those with a CD70 tumor proportion score (TPS) of 50% or higher exhibited a 50% overall response rate (ORR). Specifically, three out of six RCC patients with a TPS of 50% or more responded to the treatment, while two achieved confirmed responses after a standard lymphodepletion regimen and an 80 million CAR-T cell dose.

CEO David Chang described the efficacy results of ALLO-316 as "unprecedented.” This sentiment was echoed by Oppenheimer analysts who noted the significant T-cell expansion observed, which surpassed that in other solid tumor CAR-T trials. They highlighted that T-cell expansion occurred by day 10, effectively eliminating CD70-positive host T-cells while sparing CD70-negative cells. These findings suggest that Allogene’s Dagger technology could be a promising next-generation allogeneic platform, potentially reducing or eliminating the need for extensive lymphodepletion.

Despite these positive outcomes, the trial reported three Grade 5 treatment-related adverse events. These included a case of cardiogenic shock, a fatal sepsis infection from a drug-resistant Klebsiella pneumoniae strain, and a death attributed to "failure to thrive" 16 months post-treatment. The sepsis case involved a participant who had a history of muscle abscess and bacteremia from the same strain and was undergoing anti-inflammatory treatment for hyperinflammation. The third case involved an individual whose cancer remained stable at a 12-month check-up, but who had no subsequent scans before their death.

Addressing these adverse events, CEO David Chang emphasized the complexity of such instances in oncology patients with advanced diseases, noting that factors like underlying conditions and dosing significantly confound the incidents. He acknowledged the intricate nature of these events, highlighting the necessity of understanding the balance between dose, safety, and efficacy.

In addition to ALLO-316, Allogene is progressing with the development of ALLO-329. This CAR-T therapy targets CD19 positive B cells and CD70 positive T cells, incorporating Dagger technology similar to ALLO-316. This technology endows AlloCAR T cells with a receptor that targets and depletes CD70-positive cells in patients while masking CD70 on the AlloCAR T cells to prevent self-targeting.

During a discussion with an analyst, Chang addressed concerns about whether Dagger technology might contribute to the Grade 5 events or influence the overall safety profile. He explained that while the technology enhances the pharmacodynamic effect of CAR T cells, the development of new therapies inherently involves balancing dose, safety, and efficacy. This methodology will continue to guide their Phase I studies as they advance the ALLO-329 program.

Overall, the mixed results from Allogene's trials underscore the potential and challenges of harnessing CAR-T therapies for solid tumors. While the efficacy of ALLO-316 presents a significant advancement, the associated adverse events highlight the complexities and risks involved, necessitating careful consideration and further investigation as the company progresses with its immunotherapy programs.

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