CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia

By R. Brentjens, M. Davila, I. Rivière, Jae H. Park, Xiuyan Wang, L. Cowell, S. Bartido, J. Stefanski, Clare Taylor, M. Olszewska and 15 more. Science Translational Medicine, 2013

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Five adults with chemotherapy-refractory B-ALL were induced into molecular remissions after treatment with CD19 CAR-targeted T cells. CARving a Niche for Cancer Immunotherapy Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells that fend off infection. It’s most common in children but—as with many diseases that primarily affect children—has a much worse prognosis when it affects adults. Adults with relapsed disease have a very low chance of survival, and new therapies are desperately needed. Now, Brentjens et al. test T cells engineered to target CD19, which is expressed on both healthy B lymphocytes and B-ALL cells, in five chemotherapy-refractory adult B-ALL patients. Here, the authors treat patients with the patients’ own T cells altered to express not only CD19 but also a fusion of the costimulatory molecule CD28 with CD3ζ chain—so-called “second-generation chimeric antigen receptor (CAR) T cells.” All patients treated with these cells achieved tumor eradication and complete remission. These CAR T cells were well tolerated, although there was substantial cytokine release in some patients that correlated to tumor burden. These patients were treated with steroid therapy. Long-term follow-up in four of these patients was not possible because the CAR T cell therapy allowed these patients to be eligible for subsequent hematopoietic stem cell transplant (HSCT), which resulted in restored hematopoiesis. The remaining patient experienced a relapse of CD19+ cells that coincided with the lack of persistence of the CAR T cells from circulation. These data suggest that subsequent transfusions should be considered for patients unable to undergo HSCT. Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD− complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell–mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.

Subfields: Immunology, Oncology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/4872cac6774b7e7958e936e000fa5e42e92130c5

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Citations in the corpus

Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies (2014, result): “More than 70% of these patients had relapsed after allogeneic stem cell transplant, and none experience graft versus host disease despite a median donor T cell chimerism of 100%.15 Other groups also have reported striking efficacy of CAR-modified T cells in relapsed/refractory CLL and ALL.8,10,16”
Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia (2014, methodology): “19-28z CAR T cells were harvested, transduced, formulated, and released as previously described (1, 6, 23).”
Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses (2018, neutral): “Despite these encouraging results, safety and efficacy continue to be major hurdles that hinder CAR T cell therapy development (Brentjens et al., 2013; Kochenderfer et al., 2012; Morgan et al., 2010; Scholler et al., 2012).”
Gene therapy comes of age (2018, positive): “CAR-T cells have had a large impact on the treatment of certain cancers (139), and this success provides a foundation for future T cell–based therapies for other cancers and other diseases such as autoimmune disorders and AIDS (5, 140).”
Precision Tumor Recognition by T Cells With Combinatorial Antigen Sensing Circuits (2016, neutral): “Even in this successful treatment, however, normal B cells are targeted and eradicated (Brentjens et al., 2013; Grupp et al., 2013; Porter et al., 2011).”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “%) and durability of response that are unprecedented in acute (Brentjens et al., 2013; Maude et al., 2014; Turtle et al., 2016) and chronic leukemia (Kalos et al., 2011).”
Engineering T cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors (2016, neutral): “Particular subresponses can contribute to toxic side effects (Barrett et al., 2014b; Brentjens et al., 2013; Grupp et al., 2013; Porter et al., 2011), which in some cases can be as dangerous as the disease itself (Davila et al.”