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

Abstract

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.

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

“…14,20,23–25 Toxicity has been associated with acute, massive cytokine release in some immunotherapeutics, such as CAR T-cells. 49 Cytokines were not monitored in this study as their importance in a tumor-free animal is questionable. In most primates, cellular immunity rapidly contracted after boosting.…”

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

“…7 High-dose corticosteroids have been used in patients, although there is some evidence that they may have a detrimental effect on T cell proliferation; therefore, their use is reserved for management of continuing severe CRS and/or severe neurologic toxicity. 10 Predictive biomarkers of which patients are likely to experience CRS are being explored. 11 More extensive reviews of the grading and management of CRS have been published, 7,12 and the algorithms for clinical management are still in development by the various sponsors of CAR T cell therapies.…”

Recent advances in T‐cell immunotherapy for haematological malignancies

“…(Sadelain 2015) Several groups have reported CR rates as high as 90% in ALL after administration of a single dose of CD19-CAR T-cells following lymphodepleting chemotherapy, even in heavily pre-treated children and adults. (Davila et al 2014, Lee et al 2015, Maude et al 2014) The success of CD19-specific T-cells in early phase trials has resulted in the designation of “FDA breakthrough status” and commercialization efforts. (June et al 2015, Sadelain 2015) There are currently 45 actively enrolling clinical trials targeting CD19 with CAR T-cells.…”

“…(Davila et al 2014, Park et al 2016). Of 45 evaluable patients with morphological relapse or MRD, 37 achieved or maintained morphological CR, with no detectable MRD in 30.…”

“…(Rooney et al 2014, Sadelain 2015, Vonderheide and June 2014) Indeed, this is an exciting time in the field of T-cell immunotherapy with in vitro discoveries paving the way for bench-to-bedside translation and resulting in remarkable clinical responses in a variety of haematological malignancies. In particular, adoptively transferred T-cells genetically modified to express CD19 CARs have shown great promise (Davila et al 2014, Lee et al 2015, Maude et al 2014), although some haematological malignancies remain recalcitrant. For these tumours, combination immunotherapeutic approaches are being investigated and may prove beneficial.…”