TRBC1-directed CAR-T AUTO4 Achieves Responses in R/R Peripheral T-Cell Lymphoma

Autolus Therapeutics’ AUTO4, an investigational TRBC1-directed chimeric antigen receptor T-cell (CAR-T) therapy being evaluated in the phase 1/2 LibrA T1 study clinical trial (NCT03590574), has demonstrated the ability to produce responses among patients with relapsed/refractory (r/r) peripheral T-cell lymphoma (PTCL).¹

Among 4 patients who were treated at the highest dose level evaluated (450x10⁶ cells) using a manufacturing process referred to as Process A, all 4 patients achieved responses. One of these patients achieved a complete metabolic response (CMR) that has been sustained at 15 months posttreatment and another patient achieved a CMR that has been sustained at 18 months posttreatment, as of the April 28, 2023, data cutoff. Autolus Therapeutics noted that CAR T-cells were observed in the lymph nodes of the patients, suggesting fast homing to the tumor location. Ten patients in total received treatment with AUTO4 manufactured by Process A and an additional 3 patients received AUTO4 manufactured by a different process referred to as Process B; although, no efficacy data was reported for the latter group because their median follow-up time is less than 3 months. In terms of safety, Autolus Therapeutics reported AUTO4 to be well-tolerated; no dose-limiting toxicities were observed.

“There are limited options for patients with PTCL, so new treatments for this aggressive malignancy are desperately needed,” Kate Cwynarski, PhD, the chief investigator of the trial at University College London Hospitals NHS Foundation Trust, London, said in a statement.¹ “The LibrA T1 study of AUTO4 is a novel approach using a CAR T-cell designed to selectively target and eliminate T cells that include the malignant clone which harbors the TRBC1 receptor, while preserving the T-cell compartment with the TRBC2 receptor which helps to maintain immune-competence. AUTO4 is well tolerated and the data to date in this early phase study are very promising.”

Autolus Therapeutics lists AUTO4 as a complement to 1 of its other investigational CAR-T therapies, AUTO5. AUTO5 is intended to treat PTCL by targeting TRBC2.² It is currently in preclinical development. Both AUTO4 and AUTO5 are expected to operate in a way that preserves some healthy T-cell function, thus preventing patients from becoming fully immunocompromised by the therapies. Both products also include RQR8, a “safety switch” intended to allow for elimination of the CAR T-cells in the event of severe toxicity.

“AUTO4, with its unique targeting mechanism, represents an opportunity for advanced programmed T-cell therapies that will make a difference in patients who traditionally suffer from severe immunosuppression as a result of current therapeutic options,” Edgar Braendle, the chief development officer of Autolus Therapeutics, added to the satement.¹ “This is a trial with a small number of patients, but with all 4 patients at the highest dose in the study achieving a response and 2 out of the 4 remaining in a complete metabolic response beyond 12 months, AUTO4 shows potential to provide a novel therapy option for PTCL patients.”

Autolus Therapeutics’ most advanced-stage product is obecabatagene autoleucel (obe-cel; AUTO1), an investigational autologous CD19-directed CAR-T therapy currently being evaluated for the treatment of adults with r/r B-cell acute lymphoblastic leukemia in the pivotal phase 2 FELIX clinical trial (NCT04404660).³ Results from FELIX were recently presented at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois, by Claire Roddie, MD, PhD, FRCPath, MBChB, MRCP, an associate professor in haemato-oncology at University College London. The data showed that among 94 patients who were treated with obe-cel in the study, 76% achieved either a complete remission (CR) (54.3%) or a CR with incomplete blood count recovery (21.3%). At the conference, CGTLive™’s sister publication OncLive™ interviewed Roddie about the findings. In addition to the efficacy data, she discussed obe-cel's novel fast off-rate CD19 binding domain and how it could potentially help to reduce toxicity.

“...We know that other products on the market for adult acute lymphoblastic leukemia have got significant toxicity profiles and that's actually really difficult for us physicians to manage and particularly difficult for the patients and their families,” Roddie said. “It makes it difficult to anticipate or imagine a clinical world where we can give these comfortably as outpatient therapies, which is obviously where [we want to go]—we want to be able to improve the patient experience, quality of life, etc. And so, I think that's where obe-cel comes into this because the toxicity profile is so much less difficult for patients to tolerate—even patients with lots and lots of disease—and I think that's its biggest selling point. From the perspective of just safely navigating patients through this therapy, it’s much more straightforward.”

REFERENCES
1. Autolus Therapeutics presents positive results from AUTO4 in relapsed/refractory TRBC1-positive peripheral T-cell lymphoma. News release. Autolus Therapeutics plc. June 16, 2023. Accessed June 26, 2023. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-presents-positive-results-auto4
2. Our products. Autolus Therapeutics. Website. Accessed June 26, 2023. https://www.autolus.com/pipeline/our-products/
3. Roddie C, Sandhu KS, Tholouli E, et al. Safety and efficacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): Top line results of the pivotal FELIX study. Presented at: the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois. Abstract #7000