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Objective: Allogeneic stem cell transplantation (allo‐SCT) may have a curative potential due to the graft versus lymphoma effect. In this study, we aimed to compare transplant outcomes between refractory‐T‐NHL (ref‐NHL) and Chemosensitive‐T‐NHL (CS‐T‐NHL). Materials and Methods: We retrospectively reviewed the records of 26 ref‐NHL and 29 CS‐T‐NHL consecutive patients who underwent allo‐SCT at our center and compared the transplant outcomes between the groups. Results: All patients were heavily pretreated with 27% of patients relapsing post‐auto‐SCT and two patients in the ref‐T‐NHL post‐allo‐SCT. Patients were transplanted mainly from unrelated donors. There were no differences in leucocytes and platelet engraftment between the two groups. At 3 years, the relapse incidence was 34% in Ref‐TNHL and 19% in CS‐TNHL (p =.33), with non‐relapse mortality rates of 28% and 22%, respectively (p =.52). Female patients and those with a previous auto‐SCT had lower relapse incidence (p =.045, p =.003). The 3‐year overall survival was 39% in Ref‐TNHL and 56% in CS‐TNHL (p =.15). Trends for improved progression‐free survival (PFS) and graft‐versus‐host disease relapse‐free survival (GRFS) were observed in the CS‐TNHL group (PFS: 60% vs. 30%, p =.075; GRFS: 38% vs. 21%, p =.1). Conclusion: Acknowledging the retrospective nature of our study, our results indicate that allo‐SCT has a curative potential in patients with T‐NHL even in refractory status. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptors (CARs) are used to recognize highly specific antigens ("mugshots") to target immune effectors ("policemen") against cancer cells. Whereas this new immunotherapy has already set novel standards in the treatment of some specific types of blood cancer, it has not yet been successful with most blood (and solid) cancers for different reasons. In this work, the authors investigated the possibility of using a specific antigen called CD45 as target for CAR therapies. CD45 stands out by being present on all blood cells and therefore represents a promising target in any type of blood cancer. However, immune cells themselves also harbor CD45 at their cell surface, which is expected to lead to either inactivity of the CAR or self-killing of immune cells. To avoid these problems the Hamburg group used a trick—they applied the CRISPR/Cas gene scissors and thus produced CD45-knockout (CD45ko) immune-effector cells. Even though CD45 had been supposed to be important for the functionality of immune-effector cells, the authors observed excellent survival, proliferation and killing activities of their CD45ko CAR cells, independent of the targeted cancer-cell population. Their results thus provide initial proof-of-concept for the potential usefulness of CD45ko/CD45-CAR immune cells to target blood cancer. Background: CAR-T cell therapy has shown impressive results and is now part of standard-of-care treatment of B-lineage malignancies, whereas the treatment of myeloid diseases has been limited by the lack of suitable targets. CD45 is expressed on almost all types of blood cells including myeloid leukemia cells, but not on non-hematopoietic tissue, making it a potential target for CAR-directed therapy. Because of its high expression on T and NK cells, fratricide is expected to hinder CD45CAR-mediated therapy. Due to its important roles in effector cell activation, signal transduction and cytotoxicity, CD45 knockout aimed at preventing fratricide in T and NK cells has been expected to lead to considerable functional impairment. Methods: CD45 knockout was established on T and NK cell lines using CRISPR/Cas9-RNPs and electroporation, and the successful protocol was transferred to primary T cells. A combined protocol was developed enabling CD45 knockout and retroviral transduction with a third-generation CAR targeting CD45 or CD19. The functionality of CD45ko effector cells, CD45ko/CD45CAR-T and CD45ko/CD19CAR-T cells was studied using proliferation as well as short- and long-term cytotoxicity assays. Results: As expected, the introduction of a CD45-CAR into T cells resulted in potent fratricide that can be avoided by CD45 knockout. Unexpectedly, the latter had no negative impact on T- and NK-cell proliferation in vitro. Moreover, CD45ko/CD45CAR-T cells showed potent cytotoxicity against CD45-expressing AML and lymphoma cell lines in short-term and long-term co-culture assays. A pronounced cytotoxicity of CD45ko/CD45CAR-T cells was maintained even after four weeks of culture. In a further setup, we confirmed the conserved functionality of CD45ko cells using a CD19-CAR. Again, the proliferation and cytotoxicity of CD45ko/CD19CAR-T cells showed no differences from those of their CD45-positive counterparts in vitro. Conclusions: We report the efficient production of highly and durably active CD45ko/CAR-T cells. CD45 knockout did not impair the functionality of CAR-T cells in vitro, irrespective of the target antigen. If their activity can be confirmed in vivo, CD45ko/CD45CAR-T cells might, for example, be useful as part of conditioning regimens prior to stem cell transplantation. [ABSTRACT FROM AUTHOR]