Qin, Hong

Background: A diagnosis of cancer creates a stressful situation owing to the uncertainties related to the thought of possible suffering from complications associated with treatment toxicities, the fear of not responding to the prescribed treatment, or death. The prevalence of mental health disorders is relatively higher in cancer patients vis-à-vis the general population. Methods: We performed a retrospective cohort study to evaluate the impact of mental health disorders on outcomes of relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR T-cell) therapy using data from the TriNetX research network. Results: A total of 1587 patients met the inclusion criteria (858 with a mental health diagnosis and 729 without). After propensity score matching for age and gender, 1320 patients were included in the analysis (660 in each group). The 1-year OS was higher in patients without a mental health disorder (76.0% versus 69.4%, P = 0.004). Patients with mental health disorders had a higher incidence of cytokine release syndrome (all grades) compared with those without (35.5% versus 27.6%, P < 0.001) and immune effector cell-associated neurotoxicity syndrome (all grades) (16.8% versus 10.1%, P < 0.001). Conclusions: These findings emphasize the importance of thorough psychiatric evaluation and management in patients receiving CAR T-cell therapy. Patients with mental health disorders may need significant assistance with coordinating medical services to better adhere to required care management. Future studies are needed to help determine whether preventive and real-time mental health interventions can favorably impact outcomes of these patients.

Abstract Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of B-cell malignancies. Despite the clinical success of CD19-targeted approaches, relapsed/refractory (R/R) disease—often driven by antigen loss or immune escape—remains a major challenge. To overcome this, we developed a novel CAR-T cell therapy targeting BAFF-R, a receptor consistently expressed in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. We developed a new anti-BAFF-R monoclonal antibody and engineered the MC10029 CAR construct using its scFv. Antigen-specific cytotoxicity was validated in both in vitro and in vivo models, including Nalm-6 (leukemia) and Z138 (lymphoma), and CD19-knockout tumor cells to model (R/R) disease. MC10029 CAR-T cells were generated from healthy donors and CLL patients, and their cytotoxicity was evaluated against MEC-1, a CLL cell line, as well as autologous CLL patient tumor samples. These studies demonstrated potent and specific antitumor efficacy. We transitioned to clinical-grade production, using GMP-compliant lentivirus to manufacture MC10029 CAR-T cells under regulatory guidelines. With FDA IND approval, we initiated a Phase 1 clinical trial to evaluate safety and dosing. Our first patient, treated with a low-dose, single infusion, achieved a complete metabolic response within 2 months. The therapy is well tolerated, with no severe advent events such as cytokine release syndrome or neurotoxicity, supporting both the safety and efficacy of the therapy. Conclusion: This study represents Mayo Clinic’s first homegrown CAR-T cell therapy, developed entirely in-house—from antibody discovery and CAR design to GMP manufacturing and clinical trial—marking a significant step toward personalized, next-generation immunotherapy for B-cell malignancies. Citation Format: Yan Luo, Shaohua Guo, Yaqing Qie, Martha E. Gadd, Tanya Hundal, Hemant S. Murthy, Mohamed A. Kharfan-Dabaja, Hong Qin. From gene to bedside: Mayo Clinic’s first-in-house BAFF-R CAR-T [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3719.

Abstract Several allogeneic CAR T-cell therapies are in clinical trials to evaluate safety, many of which rely on CRISPR/Cas-based genome editing. However, the Cas enzyme’s random repair mechanism elevates the risk of undesired, off-target effects, posing a challenge for safe allogeneic CAR T-cell generation. To mitigate the risk of therapy-related oncogenesis, we sought to pursue an alternative safe strategy to manufacture allogeneic CAR T-cells distinct from the preexisting ones in the clinic. We have developed a CRISPR RNA (crRNA) targeting T-cell receptor beta constant (TRBC) gene, which in conjunction with AsCas12a Ultra enzyme, causes site-specific editing by eliciting a predictable microhomology-mediated end joining (MMEJ) DNA repair pathway, which mitigates off-targeting risk. Targeted amplicon sequencing was employed to evaluate off-targeting and repair mechanisms. Graft versus host alloreactivity as well as CAR T persistence was evaluated using immunocompromised mice. In vivo tumor challenge study was conducted for over 3 months. Engraftment confirmation was done using immunohistochemistry and flow cytometry. Interestingly while evaluating the edited T-cells, we sequestered a unique T-cell population that showed TCR disruption yet remained CD3-positive and did not cause in vivo alloreactivity. These CD3-Retained, Allogeneically Functioning T-cells (CRAFT-cells) showed a similar growth rate as unedited T-cells and were then used as a platform to produce CD19-targeted CAR T-cells and BAFF-R-targeted CAR T-cells. When compared to the standard CD3-disrupted allogeneic CAR T-cells, CRAFT CAR T-cells displayed an equally robust cytotoxicity while possessing a safer genomic profile. CRAFT CAR T-cells could function as effector cells for bispecific T-cell engager (BiTE) and induce CD3-dependent cytotoxicity against tumor cells. Pertinently, CRAFT CAR T-cells as opposed to CD3-disrupted CAR T-cells, were present in mouse xenografts without alloreactivity. Having the onset of MMEJ-directed repair and minimal off-targeting, positions this CRAFT crRNA to generate safer allogeneic CAR T-cells with an overall reduced genotoxic profile in a clinical setting. This unique CRAFT CAR T-cell population displays in vivo persistence. Additionally, CRAFT CAR T can be combined with BiTE therapy, offering a promising and potentially more durable alternative to preexisting ex vivo allogeneic CAR T-cell therapies. Citation Format: Tanya Hundal, Yan Luo, Yaqing Qie, Martha E. Gadd, Shaohua Guo, Mohamed A. Kharfan-Dabaja, Hong Qin. CD3-positive allogeneic CAR T-cells: A novel platform with persistence, BiTE-capture, and no alloreactivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4283.