CAR-T cell therapy is rapidly advancing in the field of hematologic malignancies, including significant progress in the treatment of T-cell lymphomas. However, challenges such as relapse, off-target effects, and viral infections still need to be addressed to further optimize the effectiveness of CAR-T cell therapy. At the recent 2024 European Hematology Association (EHA) Annual Meeting, the research team led by Professor Jing Pan from Beijing GoBroad Boren Hospital presented notable findings on these issues, which were selected for oral presentations. "Oncology Frontier - Hematology Frontier" conducted an on-site interview with Professor Jing Pan to discuss and interpret these studies, providing valuable guidance and practical recommendations for CAR-T therapy in clinical T-cell lymphoma treatment.Study Overview
Background Relapsed/refractory acute T-cell lymphoblastic leukemia (r/r T-ALL) lacks effective salvage therapies and has poor prognosis. Recently, CD7-targeted CAR-T cell therapy has shown efficacy in r/r T-ALL, but CD7-negative relapse is common. CD5 is expressed on blasts in over 80% of T-ALL patients and can serve as an alternative target for CAR-T therapy in patients relapsing after CD7 CAR-T therapy or with low CD7 expression.
Objective To evaluate the use of donor-derived CD5 gene knockout CD5 CAR-T cells in the treatment of r/r T-ALL.
Methods In this single-center Phase 1 study (NCT05032599), CD5+ r/r T-ALL patients received CD5 CAR-T cells (using CRISPR-Cas9 to knockout the CD5 gene). The CAR-T cells were derived from previous hematopoietic stem cell transplant (HSCT) donors (Cohort A) or new matched donors (Cohort B) (Dai et al. Mol Ther 2021;29:2707-2722). Using the Bayesian Optimal Interval 12 (BOIN12) design, two target doses (1-2×10^6/kg) were explored in both cohorts to determine the optimal biological dose (OBD). Patients received a lower dose of 0.5×10^6 (±20%)/kg if the number of prepared CD5 CAR-T cells was insufficient. The primary endpoint was safety, and the secondary endpoint was efficacy. Patients achieving complete remission (CR) after CD5 CAR-T infusion were recommended to undergo HSCT as consolidation therapy. All patients or their guardians provided written informed consent before screening.
Results From October 8, 2021, to March 21, 2023, 19 patients were enrolled, and 16 patients received CD5 CAR-T cell infusions, including 11 in Cohort A (7 at the target dose) and 5 in Cohort B (3 at the target dose). Ten patients (63%) relapsed from prior CD7 CAR-T cell therapy, with CD7 CAR-T cells detectable in 5 patients.
Adverse events (AEs) within 30 days included grade 3-4 cytopenia (100%, with 92% occurring before lymphodepletion), grade 1-2 cytokine release syndrome (75%), grade 1-2 neurotoxicity (25%), grade 1 skin graft-versus-host disease (GVHD) (69%), and one grade 3 infection (6%). No dose-limiting toxicities (DLTs) occurred.
All 16 patients (100%) achieved complete remission with incomplete hematologic recovery (CRi) by day 30 post-infusion. As of July 31, 2023, with a median follow-up of 14.3 months (IQR, 6.2-19.7), four patients received SCT on a median of 35 days post-infusion (IQR, 31-40), with three in disease-free survival and one death due to fungal infection. Among the 12 patients who did not undergo SCT (7 refused, 3 relapsed before SCT, 2 died during SCT conditioning), two remained in remission, three relapsed, five died of infections (2 from EBV and 3 from bacterial infections), and two died of thrombotic microangiopathy. Half of the grade 5 infections occurred in patients with coexisting CD7 CAR-T cells who did not receive SCT consolidation. Low levels of CD7 CAR-T cells did not affect the expansion of CD5 CAR-T cells, which remained dominant until the last follow-up. CD5+ lymphocytes decreased while CD5- lymphocytes increased, partly from CD5 gene editing.
Conclusion CD5 CAR-T cell therapy effectively induces complete remission in r/r T-ALL patients. Despite significant efficacy, patients who did not receive subsequent SCT consolidation had limited duration of remission and increased risk of severe infections, particularly those previously treated with CD7 CAR-T therapy. Combining CD5 CAR-T therapy with SCT consolidation may improve patient prognosis.
Expert Interview
Oncology Frontier – Hematology Frontier: You have two studies selected for oral presentation at this year’s EHA meeting, which is impressive. Could you first introduce the background and main results of the study on CD5 CAR-T cell therapy for pediatric and adult relapsed/refractory acute T-cell lymphoblastic leukemia (r/r T-ALL)?
Professor Jing Pan: The clinical trial on CD5 CAR-T therapy for r/r T-ALL began in 2019. Our team observed that some patients experienced CD7-negative relapse approximately six months after CD7 CAR-T therapy. Off-target relapse is a challenge in all CAR-T treatments. To address this, we collaborated with Reindeer Biotech, who were conducting preclinical studies on CD5 CAR-T and had published related articles. This collaboration provided new insights for our clinical application. We utilized their preclinical data to translate it into clinical practice and successfully applied for the CD5 CAR-T clinical study.
The study has been ongoing since 2019, and we presented the complete data at this EHA meeting. We enrolled 19 patients, with 16 successfully completing CAR-T infusions. Remarkably, within the first month of treatment, the risk to patients was relatively low, with an overall response rate of 100%, and almost all patients achieved remission. Most of the enrolled patients were those who relapsed with CD7-negative disease after CD7 CAR-T therapy. Therefore, CD5 CAR-T therapy is viewed as a salvage strategy for patients who failed CD7 CAR-T therapy. This study was designed based on this background.
Oncology Frontier – Hematology Frontier: Based on the study results, what are your prospects for combining CD5 CAR-T cell therapy with hematopoietic stem cell transplantation (SCT) for r/r T-ALL? What are your team’s future research plans for this treatment approach?
Professor Jing Pan: Over the past three years of research, we observed two key phenomena: First, CD5 CAR-T therapy provides an effective supplement to address off-target relapse, particularly in CD7 CAR-T therapy. Thus, CD5 CAR-T currently serves as a complementary approach for patients who fail CD7 CAR-T therapy. However, in cases of T-ALL relapse, if CD5 expression is superior to CD7, CD5 CAR-T could be considered. From a safety perspective, it is relatively safe as a bridging therapy to transplantation. In the future, we may explore the use of CD5 CAR-T not just as a salvage therapy but also based on the patient’s expression profile to select the most appropriate CAR-T target.
Second, we noticed differences in immune reconstitution between patients treated with CD5 CAR-T and those treated with CD7 CAR-T. Normal CD7-negative T cells account for about 10% in the human body, and during T cell reconstitution, especially without transplantation, CD7-negative T cells often proliferate quickly. However, after CD5 CAR-T therapy, patients almost lack normal CD5-negative cells. In our other study presented at this conference on viral activation, we found that long-term follow-up of CD5 CAR-T patients in remission showed very slow growth of CD5-negative cells, mainly from gene-edited products with inferior function compared to normal CD7-negative T cells. Based on this finding, we recommend bridging transplantation after CD5 CAR-T therapy to promote immune reconstitution, as the lack of normal CD5-negative T cells could lead to severe infections. This is another important message we aim to convey through this presentation.
