Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia

By M. Davila, I. Rivière, Xiuyan Wang, S. Bartido, Jae H. Park, K. Curran, S. Chung, J. Stefanski, Oriana Bórquez-Ojeda, M. Olszewska and 22 more. Science Translational Medicine, 2014

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CD19 CAR T cell therapy induces complete remissions in 88% of 16 adult patients with relapsed or refractory acute lymphoblastic leukemia. CARving Out a Niche for CAR T Cell Immunotherapy Relapsed or refractory B acute lymphoblastic leukemia (B-ALL) in adults has a poor prognosis, with an expected median survival of less than 6 months. An emerging therapy for adult B-ALL is through T cells that target tumor cells with chimeric antigen receptors (CARs). Davila et al. now report the results of a phase 1 clinical trial of CAR T cells in 16 relapsed or refractory adult patients. The CD19-targeting CAR T cell therapy resulted in an 88% complete response rate, which allowed most of the patients to transition to allogeneic hematopoietic stem cell transplantation—the current standard of care. Moreover, the authors carefully characterized cytokine release syndrome (CRS), which is a series of toxicities associated with CAR T cell therapy. They found that serum C-reactive protein (CRP) associated with the severity of CRS, which should allow for identification of the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the CRS. This is especially important because treatment for CRS may limit the efficacy of the CAR T cell therapy. These data support the need for further multicenter trials for CAR T cell therapy. We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome–positive (Ph+) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/6636c4a83802a4f7b8fad8720c1edcce94d35626

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Citations in the corpus

Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management (2018, background): “Intubation and mechanical ventilation may be required for airway protection in obtunded patients [9,11,21].”
FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome (2018, background): “Fever and tachycardia reportedly resolved within hours after infusion of tocilizumab [2, 5, 11, 14], but resolution of hypotension and organ Table 1.”
Gene therapy clinical trials worldwide to 2017: An update (2018, background): “Since the 2011 report in the New England Journal of Medicine that described one patient who went into complete remission following an infusion of transduced autologous T cells, modified to express a CAR with specificity for the B‐cell antigen CD19,(19) there have been hundreds of patients treated in”
Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. (2016, background): “Case 1 Pre-CAR-T cells Flow cytometry BMMC Abnormal lymphoblasts expressing CD45, CD19, CD22, CD38, HLA-DR, CD15, CD33, CD13 (dim), and TdT (dim) Karyotype BMMC 46,XX,t(4;11)(q21;q23),add(9)(p12)[cp20] FISH BMMC MLL rearranged IGH gene sequencing BMMC Index clone identified Day 22 after CAR-T cells ”
Engineering T cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors (2016, neutral): “, 2011), which in some cases can be as dangerous as the disease itself (Davila et al., 2014; Lamers et al., 2006; Magee and Snook, 2014; Morgan et al., 2010; Zhao et al., 2009).”
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “Then, CASP1 is activated via pyroptosis releasing factor, which cleaves GSDMD in macrophages, causing the release of cytokine and cytokine release syndrome (CRS), a serious side event characterized by fever, hypotension, and respiratory failure.(422) Thus, the development of more efficient drugs cau”
Toxicities of chimeric antigen receptor T cells: recognition and management. (2016, positive): “Some evidence suggests that corticosteroids may inhibit CAR T-cell persistence and antimalignancy efficacy, as reported previously in ALL patients following anti-CD19 CAR T-cell infusion.(4,7) For this reason, corticosteroid therapy has been reserved for use following failure of tocilizumab to ameli”
Current concepts in the diagnosis and management of cytokine release syndrome. (2014, background): “For this reason, fold increases, net increases, or rate of change in cytokine levels may provide better correlates of CRS severity than absolute cytokine levels.(26) Third, diagnostic utility could require a profile of several different cytokines rather than changes in only 1 level.”