From ChatGPT: Without CXCR4, T cells—including CPTX-2309–transfected ones—are unlikely to efficiently home to the bone marrow. If BM trafficking is crucial to the therapy's success, co-expression of CXCR4 or modification to preserve/enhance its signaling would be necessary.
''As of April 1, 2025, all patients completed the 2-month follow-up, with the first two patients completing the 3-month follow-up. Patient 1 attained a stringent complete response with resolution of all medullary and extramedullary lesions by month 2 (appendix p 4), whereas patient 2 had a stringent complete response with complete lesion resolution by day 28 (appendix p 4). Patients 3 and 4 had partial responses, with tumour lesions reduced and minimal residual disease negativity reached in the bone marrow by day 28 (appendix p 4, 9). At the 2-month follow-up, serum protein electrophoresis and free light chain concentrations (appendix p 9) returned to normal in patient 3 and were further reduced in patient 4.
CAR T cells in peripheral blood were first detected on days 4–8 and peaked on days 10–17, and were also detectable in the bone marrow, tumour tissues, pleural effusions, and CSF (figure D; appendix pp 5, 9). In patient 2, immunohistochemistry of baseline and day 10 tumour biopsies revealed marked reduction of CD38+CD138+BCMA+ tumour cells alongside significant CD3+ T-cell infiltration in the tumour microenvironment (appendix p 5).
We then analysed the phenotypic profile of CAR+ T cells at the expansion peak (appendix p 5). Patient 1 had a higher proportion of CAR+ T cells with a central memory phenotype, whereas patients 2 and 4 had a greater abundance of naive and central memory CAR+ T cells. Effector and CD28–CD57+ senescent T cells were enriched in CAR+ T cells of patient 3, which corresponded to unfavourable CAR T-cell expansion. Flow cytometry of CAR T cells in peripheral blood showed a low CAR expression in CD3– lymphocytes and natural killer cells (appendix p 5). Nonetheless, off-target transduction in haematopoietic cells and other immune cells requires further study, and tumourigenicity needs to be monitored through long-term follow-up.''
This could end the transient, re-dosable (m)RNA approach for a number of companies. This would leave integrating CARs. Non-viral delivery, with site-specific integration would likely win over those working on viral delivery (+/- non site-specific integration).
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