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

Article

ADI-001 has been granted a Fast Track Designation by the FDA a potential treatment for patients with relapsed or refractory B-cell 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
Related Videos
Vivien Sheehan, MD, PhD, an associate professor of pediatrics at Emory University
John A. Charlson, MD
Judy Lieberman, MD, PhD, the endowed chair in cellular and molecular medicine at Boston Children’s Hospital
Omid Hamid, MD
Alexandra Gomez-Arteaga, MD
Brian Shaffer, MD
John Ligon, MD, an assistant professor in the department of pediatrics at the University of Florida College of Medicine
Judy Lieberman, MD, PhD, the endowed chair in cellular and molecular medicine at Boston Children’s Hospital
Alexandra Gomez Arteaga, MD
Mark Walters, MD
© 2024 MJH Life Sciences

All rights reserved.