ADI-001 Granted Fast Track Designation for Non-Hodgkin Lymphoma

The off-the-shelf CD20 CAR-modified gamma and delta T cell therapy ADI-001 has been granted a Fast Track Designation by the FDA a potential treatment for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), according to a statement from Adicet Bio, the company developing the therapy.

Promising interim findings from the study were announced in December 2021, along with a presentation at the 2021 ASH Annual Meeting detailing the design of a phase 1 study investigating the therapy (NCT04735471). At the data cutoff of November 22, 2021, there were 6 patients with heavily pretreated R/R NHL with 4 evaluable for efficacy. The objective response rate (ORR) was 75% and consisted of 2 complete responses (CR) and 1 partial response (PR). At the time of the assessment, there were no ADI-001-related serious adverse events reported, including a lack of graft-vs-host disease (GvHD), neurotoxicity, and high-grade cytokine release syndrome, which are common with other CAR T-cell therapies.

“Fast Track Designation represents an important milestone in the clinical development of ADI-001,” Chen Schor, president and chief executive officer of Adicet Bio, said in a statement. “We believe ADI-001 is unique in that it is designed to target malignant B cells by leveraging the innate and adaptive receptors found naturally on gamma delta T cells with the added benefit of an engineered anti CD20 CAR. We remain optimistic about the potential of our program and look forward to reporting additional data from the Phase 1 trial of ADI-001 in the first half of 2022.”

ADI-001 is manufactured from cells that are collected from a qualified donor and combined with AM3529, an antibody that is used to isolate and activate the gamma delta T cells that have HLA independent T cell receptors (TCR), which makes them unlikely to cause GvHD. As a result of the intrinsic benefits of these cells, ADI-001 does not require genetic engineering to remove TCRs. For ADI-001, once the gamma delta T cells are isolated, they are next transduced with a second-generation CAR specific to CD20 and stored until administration. The construct has 4-1BB and CD3 zeta signaling domains.

For the ongoing study, patients are administered a lymphodepleting regimen of fludarabine (30 mg/m² per day for 3 days) and cyclophosphamide (500 mg/m² per day for 3 days) 5 days prior to a one-time infusion of ADI-001. The protocol allows for optional pretreatment with ADI-001 following a response and safety assessment at 28 days.

The study plans to enroll 30 patients with R/R B cell NHL for the dose escalation portion of the study, which is exploring 3 dose levels, starting at 30 million CAR+ cells, followed by 100 million, and finally 300 million CAR+ cells. In part 2 of the study, approximately 36 patients will be enrolled into 3 separate cohorts stratified by disease, with cohorts for diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other subtypes of NHL. A third portion of the study will explore the addition of low-dose subcutaneous IL-2 to ADI-001. This part of the study seeks to enroll 12 patients. Part 2 and 3 will utilize the maximum tolerated dose (MRD) of ADI-001 identified in part 1 of the study.

In the interim efficacy findings, evaluable patients had received a median of 5 prior regimens. Three of the 4 patients received the lowest dose level (30 million cells) and 1 received the second dose level (100 million cells) in part 1 of the study. At the lowest dose, there was 1 CR and 1 PR, which was a near CR. The single patient evaluable at the second dose had achieved a CR. One of the patients who experienced a CR had received a prior autologous CD19-directed CAR T-cell therapy. This patient had DLBCL.

In a biomarker assessment, there was a significant increase observed in circulating IL-15 following lymphodepletion. ADI-001 expansion and proliferation was noted by quantitative polymerase chain reaction and by flow cytometry. IL-2 and IL-8 were observed in the first 14 days following administration of ADI-001, which is an indication of ADI-001 activation. There were no meaningful IL-6 increases seen following ADI-001 treatment, except for 1 patient who developed a COVID-19 infection.

The phase 1 study continues to enroll participants with R/R NHL treated with at least 2 prior regimens, including treatment with an anti-CD20 antibody. ECOG performance status of 0 or 1 will be required for all patients as is adequate hematologic and organ function. Those with CD20-negative disease are excluded from the study and patients can receive a prior anti-CD19 CAR T-cell therapy but it must have been received more than 6 weeks prior to study entry.

The primary end point of part 1 of the study is the incidence of dose limiting toxicities and discovery of the MTD. For part 2 and 3, the safety and efficacy of the MTD or maximum administered dose of ADI-001 will be further explored. Secondary objectives will examine pharmacokinetics, immunogenicity, and antitumor activity. The study is currently enrolling at 5 different sites in the United States.

REFERENCES

1. Adicet Bio Receives FDA Fast Track Designation for Lead Candidate ADI-001. News release. Adicet Bio. April 19, 2022. https://investor.adicetbio.com/news-releases/news-release-details/adicet-bio-receives-fda-fast-track-designation-lead-candidate

2. Adicet Bio Announces Positive Interim Clinical Data From First-Ever Allogeneic, Off-The-Shelf, Gamma Delta CAR T Investigational Cell Therapy. News release. Adicet Bio. December 6, 2021. https://investor.adicetbio.com/news-releases/news-release-details/adicet-bio-announces-positive-interim-clinical-data-first-ever

3. Neelapu SS, Hamadani M, Stevens D, et al. A Phase 1 Safety and Efficacy Study of ADI-001 Anti-CD20 CAR-Engineered Allogeneic Gamma Delta (γδ) T Cells in Adults with B Cell Malignancies, in Monotherapy and Combination with IL-2. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2834