In an effort to directly integrate CAR T cell therapy with allogeneic hematopoietic stem cell transplant (allo-HCT) and post-transplantation cyclophosphamide (PTCy; given 3 and 4 days after allo-HCT to prevent GvHD). Patterson and Khan et al. tested different sequences and timings of the combination treatment in a T cell-replete, MHC-haploidentical mouse model. When given on the same day as allo-HCT (day 0) or 5 days after (but not 9 or 14 days after), CD19 CAR T cells could effectively clear leukemia without exacerbating CRS or compromising the function of PTCy. CAR T cells given on day 0 showed the most clinical efficacy, which was associated with a superior activation profile.
Contributed by Lauren Hitchings
ABSTRACT: Relapse limits the therapeutic efficacy both of chimeric-antigen-receptor (CAR)-T-cells and allogeneic hematopoietic cell transplantation (allo-HCT). Patients may undergo these therapies sequentially to prevent or treat relapsed malignancy. However, direct integration of the two therapies has been avoided over concerns for potential induction of graft-versus-host disease (GVHD) by allogeneic CAR-T-cells. We have shown in murine T-cell-replete MHC-haploidentical allo-HCT that suppressive mechanisms induced immediately after post-transplantation cyclophosphamide (PTCy), given on days +3/+4, prevent GVHD induction by alloreactive T-cells infused as early as day +5. Therefore, we hypothesized that allogeneic CAR-T-cells given in a similarly integrated manner in our murine MHC-haploidentical allo-HCT model may safely exert anti-tumor effects. Indeed, allogeneic anti-CD19 CAR-T cells given early after (day +5) PTCy or even prior to (day 0) PTCy cleared leukemia without exacerbating the cytokine release syndrome occurring from the MHC-haploidentical allo-HCT or interfering with PTCy-mediated GVHD prevention. Meanwhile, CAR-T-cell treatment on day +9 or +14 was safe but less effective, suggesting a limited therapeutic window. CAR-T-cells infused before PTCy were not eliminated, but surviving CAR-T-cells continued to proliferate highly and expand despite PTCy. In comparison with infusion on day +5, CAR-T-cell infusion on day 0 demonstrated superior clinical efficacy associated with earlier CAR-T-cell expansion, higher phenotypic CAR-T-cell activation, less CD4+CD25+Foxp3+ CAR-T-cell recovery, and transcriptional changes suggesting increased activation of CD4+ CAR-T-cells and more cytotoxic CD8+ CAR-T-cells. This study provides mechanistic insight into PTCy's impact on graft-versus-tumor immunity and describes novel approaches to integrate CAR-T-cells and allo-HCT that may compensate for deficiencies of each individual approach.
Author Info: (1) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (2) Center for Immuno-Oncol
Author Info: (1) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (2) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (3) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, United States. (4) National Institutes of Health, Bethesda, Maryland, United States. (5) Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (6) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (7) NIH, Bethesda, Maryland, United States. (8) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (9) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (10) Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland, Bethesda, Maryland, United States. (11) Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States. (12) National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (13) NCI, Bethesda, Maryland, United States. (14) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, United States. (15) Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States. (16) Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States.
