CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL)

Abstract

Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults. Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major preclinical and clinical priority. Adoptive cellular therapy with patient-derived human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CD19 CAR T cells) is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with multiply relapsed B-ALL. Investigative teams at several major cancer centers are currently conducting phase I clinical trials in children and/or adults with relapsed/refractory B-ALL to assess the safety and to identify the maximally tolerated dose of each group’s CD19 CAR T-cell product. All groups have reported major clinical toxicities associated with CD19 CAR T-cell treatment, including cytokine release syndrome (CRS) and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19 CAR T cells persist in vivo. Toxicities have generally been transient or manageable with supportive care measures. Some patients with life-threatening CD19 CAR T-cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T-cell proliferation. Remarkably, 67–90% of children and adults with B-ALL treated with CD19 CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission. The duration of CD19 CAR T cell persistence in vivo has varied appreciably among treated patients and likely reflects differences in the CD19 CAR constructs utilized at each institution. CD19-positive and CD19-negative B-ALL relapses after CD19 CAR T-cell treatment have occurred in some patients. Phase II trials to assess the efficacy of CD19 CAR T-cell immunotherapy in larger cohorts of patients with relapsed/refractory B-ALL are ongoing or planned.

Updates in Adult Acute Lymphoblastic Leukemia—Current Status of Antigen-targeted Treatments and Immunotherapy

“…CARs are synthetic in efforts to increase the expansion, persistence and potency of CAR T cells, and to prevent cellular exhaustion in vivo. 62,63 CD19-directed CAR-modified T cells are the most advanced engineered T cells presently used for ALL. Studies using CD19 CAR designs have been performed by several groups and showed CR rates ranging from 70-90% (Table 4).…”

Role of Cell Based Approaches in Cancer Immunotherapy

“…These studies demonstrated response in many patients. [10][11][12] Antigens like human epidermal growth factor receptor over-expressed in tumors like breast, ovarian, non small cell lung carcinoma (NSCLC), salivary gland, pancreatic and endometrial cancers are under investigation for CART cell development. [13][14][15][16][17] Till now, most of the success of CART cells is limited around hematological malignancies, a huge scope is still available for exploring new antigens, directed to eliminate metastatic, resistant and non-hematological malignancies.…”

Challenges faced in the treatment of acute lymphoblastic leukemia in adolescents and young adults

“…66 In children, adolescents, and adults, clinical trials with CAR-T therapy have demonstrated that between 67% and 90% of patients with relapsed or refractory disease can successfully achieve remission. [66][67][68] Although promising, the manner in which this therapy will change the treatment algorithm for those with relapse who have historically undergone HSCT is not yet known. Likewise, for those patients with newly diagnosed leukemia, it is not yet known what role CAR-T therapy will play and further research will be needed.…”