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.

In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

Adults with relapsed B-acute lymphoblastic leukemia (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 5 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-negative complete remissions as assessed by deep sequencing PCR. 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. Significantly, 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, ineligible for additional allo-HSCT therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell mediated cytotoxicity suggesting potential clinical benefit of additional CAR modified T cell infusions. These results demonstrate the marked anti-tumor efficacy of 19-28z CAR modified T cells in patients with relapsed/refractory B-ALL and the reliability of this novel therapy to induce profound molecular remissions, an ideal bridge to potentially curative therapy with subsequent allo-HSCT.

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CARs are recombinant receptors that provide both antigen-binding and T cell activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. Their biological functions have dramatically changed following the introduction of tri-partite receptors comprising a costimulatory domain, termed second generation CARs. These have recently demonstrated clinical benefit in patients treated with CD19-targeted autologous T cells. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors or cytokines to further enhance T cell potency, specificity and safety. CARs represent a new class of drugs with exciting potential for cancer immunotherapy.

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood-cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system-specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity. We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. .

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In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and ‘armoured’ CAR T cells are recommended.