Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia

Abstract

Summary Chimeric antigen receptor–modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre–B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×106 to 1.2×107 CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce anti-leukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor–modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.

CART‐cells merge into the fast lane of cancer care

“…We and other groups have also noted investigational cytokine activation profiles which correlate with clinical syndrome of CRS [1][2][3][4]6,32]. Effector cytokines such as INFÇ and soluble interleukin-2 receptor a (sIL2Ra) are elevated but so are cytokines traditionally associated with macrophage activation such as IL-6 and interleukin-10.…”

“…While children are initially more responsive to traditional salvage chemotherapy approaches than adults, these remissions are often not sustained and relapsed ALL remains a leading cause of cancer deaths in children [29,30]. It is this dismal prognosis and lack of conventional treatment options, which underscores the impact of the dramatic responses observed with CD19-CAR T-cell therapy in patients with relapsed and refractory ALL [1,3,4,31,32].…”

“…Given the very high levels of IL6 observed in patients with CRS and the initial observation that tocilizumab, an antibody against the IL-6 receptor, rapidly reversed fevers, hypotension, and life-threatening hypoxia in a child with CRS after CTL019 [32], the use of tocilizumab to manage CRS has become standard. Tocilizumab remains an attractive choice as it continues to be effective for most patients and has limited inherent toxicity.…”

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

“…The severity of CRS does not appear to correlate with overall disease response, but most responding patients demonstrate some degree of CRS. [3][4][5][6][7] In patients with acute lymphoblastic leukemia (ALL), CRS has been correlated with disease burden at the time of infusion, and experience has demonstrated that more potent conditioning regimens may increase the likelihood of severe CRS and/or CAR-related toxicity. 8 Patients with severe CRS can also develop a macrophage activation syndrome (MAS) reminiscent of hemophagocytic lymphohistiocytosis, as demonstrated by overlapping cytokine profiles, hyperferritinemia, and evidence of hemophagocytosis on bone marrow biopsy.…”

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

“…1–5 CARs contain an extracellular ScFv fragment recognizing tumor-associated antigens (TAAs), the CD3z intracellular T cell-activating domain and co-stimulatory domains such as those derived from CD28 and 4-1BB. Upon binding of target antigens by ScFv, the signaling domains are activated, leading to target cell killing and CAR-T cell proliferatio.…”