Neoantigen Reactive T Cell Therapy Shows Early Signs of Efficacy in NSCLC and Melanoma


Achilles Therapeutics presented updated data from CHIRON and THETIS at the 2022 ESMO immuno-oncology congress.

ATL001, a clonal neoantigen reactive T cell (cNeT) therapy, has shown some clinical activity in patients with non-small cell lung cancer (NSCLC) enrolled in the phase 1/2 CHIRON study (NCT04032847) as well as in patients with melanoma in the phase 1/2 THETIS study (NCT03997474).

“The early safety, tolerability, and durable clinical benefit in heavily pre-treated patients presented today are encouraging and illustrate the promising therapeutic potential of cNeT monotherapy. Further, the strength of our translational science platform was shown by our ability to track key elements of activity that correlated to cNeT presence,” Iraj Ali, PhD, chief executive officer, Achilles Therapeutics, said in a statement. “We look forward to providing further updates in 2023, including additional monotherapy data from CHIRON and THETIS, and initial THETIS combination data evaluating cNeT with a PD-1 checkpoint inhibitor.”

These data were presented at the ESMO Immuno-Oncology Congress 2022, taking place December 7-9 in Geneva, Switzerland. The updated data are from 8 participants in CHIRON and 6 in THETIS, which had a median of 2 prior lines of therapy. Two additional patients, 1 in each cohort, have been dosed since the cut-off date.

The cNeT cells were well-tolerated with a favorable safety profile compared to tumor infiltrating lymphocyte (TIL) therapy and less IL-2 toxicities were observed. The most common adverse events (AEs) were lymphopenia and neutropenia associated with the conditioning regimen,and there were no high-grade dose-limiting toxicities associated with IL-2. The lower dose of lymphodepletion and IL-2 may allow wider enrollment/access in patients with greater co-morbidities and effective lymphodepletion and subsequent immune reconstitution were still seen.

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In patients with NSCLC in CHIRON, investigators observed 1 partial response and 6 cases of stable disease for a 71% overall durable clinical benefit rate at 12 weeks. Half of patients with melanoma had stable disease. Investigators also observed successful engraftment and favorable cytokine profiles. The cNeT phenotype demonstrated markers associated with tissue migration and supportive to proliferation and cytotoxicity. Peak expansion was observed at 21 days after treatmnet and cNeT was deteceted beyond 12 weeks by T-cell receptor analysis.

“The partial response and stable disease observed with low doses of cNeT in this difficult to treat patient population are encouraging, and coupled with the well-tolerated safety profile, highlight a favorable therapeutic window to further dose escalate and help drive deeper, more durable responses,”professor Karl Peggs, chief medical officer, Achilles, added to the statement. “We believe this is the first time a response in lung cancer has been demonstrated using a cell therapy with a low dose conditioning and IL-2 regimen, which importantly, could expand eligibility of this therapy to include patients with comorbidities or reduced fitness that may not be candidates for traditional TIL therapy.”

Both CHIRON and THETIS are primarily evaluating treatment-emergent AEs as a primary outcome measure. Secondary outcome measures include change in tumor size, overall response rate, time to and duration of response, disease control rate, progression-free survival, and overall survival.

“In addition to the durable clinical benefit, our translational science platform begins to deliver key mechanistic insights for our cNeT therapy that are not possible with a standard TIL product, including assessment of phenotypic markers as well as proliferative and cytolytic capacity of the tumor reactive cNeT component,” Sergio Quezada, PhD, chief scientific officer, Achilles, added. “By virtue of knowing the cNeT targets and being able to characterize and track specific cNeT in the product and in the blood of patients, we can monitor cNeT dose, markers of function and exhaustion, engraftment, activation, and other features related to the patient, product, and performance in vivo.”

Achilles Therapeutics Presents Encouraging Phase I/IIa Update on Clonal Neoantigen Reactive T Cells in Advanced NSCLC and Melanoma at ESMO IO Congress 2022. News release. Achilles Therapeutics. December 6, 2022.
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