T-Cell Battle Royale: Chimeric Antigen Receptor T-cells for the Treatment of T-lineage Acute Lymphoblastic Leukemia

Advances in frontline chemotherapy regimens have been the focus of clinical research in the field for the past 30 years, and T-lineage acute lymphoblastic leukemia (T-ALL) is now curable for 90 percent of children and nearly 70 percent of young adults with contemporary pediatric chemotherapy regimens.^1,2  Despite these intensive regimens, rates of minimal residual disease (MRD), the most important risk factor for relapse, remain high across all age groups.^3,4  Approximately 15 percent of children, 25 percent of adolescents and young adults (AYAs), and 40 percent of older adults will still relapse after achieving an initial complete response (CR).^1,2,5  Once this occurs, T-ALL is incurable for most. Less than 30 percent of children and less than 10 percent of adult patients achieve long-term survival, highlighting the lack of effective salvage therapies for relapsed T-ALL.^5,6 

The dismal prognosis with existing salvage treatments for T-ALL has left many clinicians and researchers eager for the emerging possibilities of novel therapies, including immune-based therapy such as chimeric antigen receptor T-cell (CAR-T) treatments. Optimism stems from the recent progress made in the treatment of relapsed/refractory (r/r) B-lineage ALL (B-ALL), which has benefited from targeted CD19 and CD22 antibody therapy and CAR-T platforms. However, slower development of CAR-Ts for the treatment of r/r T-ALL results from challenges arising from the shared T-lineage of the malignant target and the normal cells being repurposed to fight them, as well as the natural function of T cells. These issues were discussed in more detail in a Mini Review article earlier this year in The Hematologist. During the past year, two first-in-human studies reported results of CAR-Ts for treatment of T-ALL .^7,8  We chose this topic as the Year’s Best not only because this immunotherapy has the potential to be a major clinical advancement for the treatment of T-ALL, but also because it represents the culmination of years of international preclinical work that is finally coming to clinical fruition for T-cell malignancies.

During the 2019 ASH Annual Meeting, Dr. LaQuisa Hill and colleagues from Baylor College of Medicine reported the use of a CD5-directed CAR-T construct with a CD28 costimulatory endodomain in a phase I dose escalation study of nine patients with r/r T-lineage malignancies (NCT03081910).⁷  This clinical trial was designed to evaluate the safety and feasibility of CD5-directed CAR-Ts as a “bridge” to allogeneic hematopoietic stem cell transplantation (HSCT) due to the potential for profound immunosuppression if the CAR-Ts eliminated normal T-cell subsets expressing CD5.

The researchers reported that in these nine enrolled patients with extensive prior therapy (median age, 62 years), autologous T-cells were collected successfully to create the CD5 engineered T-cells, and no residual malignant cells were detected in the CD5 CAR-T product by flow cytometry. The CD5 CAR-T product resulted in only minimal and transient fratricide. Patients were treated with a lymphodepleting chemotherapy of cyclophosphamide and fludarabine and then received CAR-Ts at two early dose levels. CAR-T expansion was observed in all patients with peak expansion in the blood one to four weeks after the CAR-T infusion. CAR-T persistence, as measured by CAR transgene levels in the blood, ranged from three weeks to six months. The impact of the engineered CAR-T product on normal T-cell numbers was evaluated by measuring CD3⁺ subsets in the blood. CD3⁺ T-cell numbers were decreased, though complete T-cell aplasia was not observed. Two patients had prolonged cytopenias at six weeks, however, and one of these patients had viral reactivation of cytomegalovirus and BK virus requiring antiviral treatment. Three patients achieved a CR (2 with T-lineage non-Hodgkin lymphoma [T-NHL] and 1 with T-ALL), but none proceeded to the planned HSCT (2 patients did not wish or were unable to proceed, and one relapsed during HSCT planning). One patient with T-NHL achieved a mixed response and received a second infusion of CAR-Ts, proceeded to transplantation, and remained in CR at day 125 post-transplantation. In summary, the investigators were able to prove that technical hurdles of T-antigen–targeted CAR-Ts can be overcome with a successful autologous T-cell collection without contamination of malignant cells, and minimal fratricide of the engineered CAR-T product. Regarding the clinical hurdle of profound immunosuppression, the engineered CAR-T product at the dose levels tested did not result in complete T-cell aplasia as anticipated. This trial is ongoing with plans to test higher cell dose levels of CD5 CAR-Ts.

In an alternative approach using CRISPR/Cas9 gene editing technology, scientists at Army Medical University in China have designed a universal CD7-directed CAR-T construct, TruUCAR GC027. Preliminary results from five patients with r/r T-ALL were presented at the 2020 American Association for Cancer Research Virtual Meeting.⁸  The T cells were collected from HLA-mismatched healthy donors, and the TruUCAR product was developed using gene editing to remove CD7 to avoid fratricide, and the T-cell receptor α chain to prevent graft-versus-host disease. All patients were treated with a six-day “preconditioning chemotherapy” followed by a single infusion of the CAR-T product. All five patients were reported to achieve a CR, and four of the five patients achieved MRD-negative remission at day 28. Three patients maintained their MRD-negative remission status at day 61, day 118, and day 161. Peak expansion of the GC027 cells was observed between weeks 1 and 2. One patient had prolonged cytopenias and developed a fungal infection that required antifungal therapy. No patients proceeded to HSCT, and no patients developed graft-versus-host disease. The clinical trial (NCT04264078) is ongoing, and the follow-up data should provide evidence of the durability of the responses and additional toxicity assessments.

The expansion of CD5 and CD7 CAR-Ts into the treatment of T-cell malignancies represents a scientific milestone for 2020 and provides encouragement that this novel paradigm may provide salvage treatment for r/r T-ALL. This work also presents new questions: Can T-cell–targeted CAR-Ts demonstrate safety, efficacy, and durability of response for the treatment of T-cell malignancies in larger scale studies? Which platform, “off the shelf” constructs, or autologous T-cell constructs, will provide a better therapeutic product? Does the gene editing for the “off the shelf” constructs create new clinical problems? Will this approach revolutionize the treatment of T-cell malignancies as it has for B-cell diseases? Will the lessons learned along the way further our understanding of and dexterity at T-cell manipulation for use in cellular immunotherapies in general? In the next year, we anticipate many patients with T-cell malignancies will be treated with CAR-T approaches (Table), and eagerly await the additional data.