Targeted cellular therapy for treatment of relapsed or refractory leukemia.

While the mainstay of treatment for high-risk or relapsed, refractory leukemia has historically revolved around allogeneic hematopoietic stem cell transplant (allo-HSCT), targeted immunotherapies have emerged as a promising therapeutic option, especially given the poor prognosis of patients who relapse after allo-HSCT. Novel cellular immunotherapies that harness the cytotoxic abilities of the immune system in a targeted manner (often called "adoptive" cell therapy), have changed the way we treat r/r hematologic malignancies and continue to change the treatment landscape given the rapid evolution of these powerful, yet sophisticated precision therapies that often offer a less toxic alternative to conventional salvage therapies. Importantly, adoptive cell therapy can be allo-HSCT-enabling or a therapeutic option for patients in whom transplantation has failed or is contraindicated. A solid understanding of the core concepts of adoptive cell therapy is necessary for stem cell transplant physicians, nurses and ancillary staff given its proximity to the transplant field as well as its inherent complexities that require specific expertise in compliant manufacturing, clinical application, and risk mitigation. Here we will review use of targeted cellular therapy for the treatment of r/r leukemia, focusing on chimeric antigen receptor T-cells (CAR T-cells) given the remarkable sustained clinical responses leading to commercial approval for several hematologic indications including leukemia, with brief discussion of other promising investigational cellular immunotherapies and special considerations for sustainability and scalability.

Feasibility and preclinical efficacy of CD7-unedited CD7 CAR T cells for T cell malignancies.

Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the ex vivo expansion of unedited CD7 CAR T cells and allowed regaining full CAR-mediated cytotoxicity in vitro and in vivo on withdrawal of the inhibitors. The unedited CD7 CAR T cells persisted long term and mediated sustained anti-leukemic activity in two mouse xenograft models of human T cell acute lymphoblastic leukemia (T-ALL) by self-selecting for CD7-, fratricide-resistant CD7 CAR T cells that were transcriptionally similar to control CD7-edited CD7 CAR T cells. Finally, we showed feasibility of cGMP manufacturing of unedited autologous CD7 CAR T cells for patients with CD7+ malignancies and initiated a phase I clinical trial (ClinicalTrials.gov: NCT03690011) using this approach. These results indicate pharmacologic inhibition of CAR signaling enables generating functional CD7 CAR T cells without additional engineering.

Replacing CAR-T cell resistance with persistence by changing a single residue.

Sustained persistence of chimeric antigen receptor T (CAR-T) cells is a key characteristic associated with long-term remission in patients with hematologic malignancies. Attempts to uncover mechanisms that enhance persistence and thus functionality will have a substantial impact in broadening application of CAR-T cell therapy, especially for solid tumors. In this issue of the JCI, Guedan et al. describe a promising strategy to limit T cell exhaustion and improve persistence by changing a single amino acid in the costimulatory domain of CD28. The authors demonstrated that this single amino acid substitution in CD28-based mesothelin CAR-T cells results in improved persistence and functionality in a xenograft model of pancreatic cancer. Furthermore, reciprocal alteration of the same residue in inducible costimulator-containing (ICOS-containing) CAR-T cells resulted in limited antitumor activity and persistence. These findings suggest that simple alterations in the costimulatory domain may enhance CAR-T cell persistence, warranting future evaluation in other CD28-costimulatory CARs in an effort to improve durable antitumor effects.

Chimeric Antigen Receptors for T-Cell Malignancies.

Development of chimeric antigen receptor (CAR)-modified T cells for the treatment of T-lineage leukemia and lymphoma has encountered several unique challenges. The most widely expressed tumor antigen targets for malignant T cells are often also expressed on non-malignant T cells. Transducing T cells with CARs targeted to these shared antigens can therefore promote over-activation or fratricide of CAR T cells, reducing their therapeutic potency. If fratricide is resolved, clinical CAR T cell activity may eliminate normal T-cell subsets and cause temporary immunosuppression. In this review, we summarize the preclinical development of CAR-based therapies for T-cell malignancies and discuss strategies to minimize toxicities associated with on-target fratricide and off-tumor activity.