Comment

In The Lancet, Daniel Lee and colleagues1 report on a novel approach for the treatment of childhood acute lymphoblastic leukaemia, with important implications for other cancers. B-lineage acute lymphoblastic leukaemia is the commonest childhood cancer, with some 400 new cases a year in the UK. Despite major advances, 15% of children do not respond to currently available treatments, including chemotherapy and stem cell transplantation, and untreatable relapse remains a leading cause of childhood cancer deaths. In adult patients, relapse is more frequent and often unsalvageable. Since such patients have often had the maximum tolerable dose of chemotherapy and radiotherapy, there is a pressing need for novel treatment strategies to treat relapse in acute lymphoblastic leukaemia. Much interest has focused on T-cell immunotherapy, using cells as a personalised, living drug. Emerging data show that immunotherapy with CD19 chimeric antigen receptor (CAR) redirected T cells can result in disease remission for patients with a range of B-lineage haematological malignancies.2–8 In this approach, T cells are genetically modified ex vivo to express a CAR consisting of the antigen-binding region of a monoclonal antibody linked to intracellular T-cell signalling domains.9 T cells expressing CARs are thus redirected to recognise and kill the tumour independent of major histocompatibility complex restriction. After modification with CAR, T cells are returned to the patient, where they can expand and effect persisting anti-tumour responses. Consequently, CAR T cells have the promise of greater potency and more durable responses compared with therapeutic monoclonal antibodies and related approaches. CD19 is an excellent target for CAR T-cell therapy: CD19 is highly expressed on more than 95% of B-lineage acute lymphoblastic leukaemia cells and normal B cells, but is absent from other cell types avoiding toxicity in non-lymphoid tissues. Other groups have shown the remarkable potential for immunotherapy with CD19CAR redirected T cells in 16 adults and two children with acute lymphoblastic leukaemia.10,11 Lee and colleagues1 confirm and extend previous data in a well designed, intention-to-treat analysis of 21 consecutive paediatric and young adult patients, the

majority of whom had a high leukaemic burden preimmunotherapy. The authors show that it was possible to generate the T-cell product at the prescribed dose in 90% of patients, illustrating the applicability of this strategy. They also define a maximum tolerated dose beyond which toxicity was unacceptably frequent. The authors observed a complete response rate of 67% (14 of 21 patients). Impressively, 12 of 20 patients (60%) became minimal residual disease negative: a much higher proportion than would be expected with salvage chemotherapy in this patient group. Additionally, they describe detection of CAR T cells in the cerebrospinal fluid in 11 of 18 assessed patients and clearance of CNS disease in two patients, suggesting that this therapy might also be effective in sanctuary sites for conventional therapies. Together with other reports,10,11 these data show unprecedented response rates of 60–80% in patients with relapsed or refractory acute lymphoblastic leukaemia across different institutions. These studies have some common factors that are probably crucial for effectiveness: lymphodepleting chemotherapy was given before CAR T-cell administration to create space in the lymphoid compartment and allow the CAR T cells to engraft and expand; a second-generation CAR, which incorporates a co-stimulatory domain, was used; and T cells were expanded in short-term culture. CAR T-cell expansion in vivo appears to be crucial and correlates with both response and toxicity. The available data suggest that response rates in acute lymphoblastic leukaemia might be significantly higher than in other B-cell malignancies such as non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. This finding was not anticipated because the rate for acute lymphoblastic leukaemia progression is greater than other B-cell malignancies, and might reflect factors such as tumour microenvironment and T-cell homing to sites of disease. The major toxicities associated with this approach include: cytokine release syndrome, the severity of which appears to correlate with disease burden and, while often severe, can be ameliorated by the interleukin-6 receptor blocking antibody tocilizumab; an unexplained transient neurotoxicity; and on-target, off-tumour depletion of normal B cells. The latter might be an acceptable price to pay for disease control in such high-risk patients.

www.thelancet.com Published online October 13, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61729-3

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Chimeric antigen receptor T cells for ALL

Leukaemic lymphoblast Published Online October 13, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61729-3 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)61403-3

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Comment

At present, it is not clear how long remission will be sustained—most responding patients have been consolidated with stem-cell transplantation. In the previous studies,10,11 the persistence of redirected T cells has been poor (maximum 2 months) and defining whether this reflects T-cell exhaustion, immunological clearance, or an alternative mechanism will be crucial for future technology development. CAR design could have an impact on how long CAR-modified T cells survive in the patient, with apparently more prolonged persistence of T cells transduced with the CAR used by the University of Pennysylvania group,11 which incorporates a 4-1BB co-stimulatory domain. The persistence of CAR T cells will be crucial to defining their future role in therapy, as a cytoreductive bridge to stemcell transplantation or a standalone therapy. It will also be crucial to understand the reasons why some patients do not respond. Potentially, CD19-CAR T-cell therapy could be of major clinical benefit to both children and adults with high-risk acute lymphoblastic leukaemia. This approach allows salvage of cases refractory to conventional therapies facilitating definitive treatment with stem-cell transplant. Beyond this, it is possible that CD19-CAR T cells might obviate the need for stem-cell transplantation with its attendant mortality, late toxicities, and cost. However, many obstacles remain to broader application. The technology for manufacturing the genetically modified T cells is complex and patient specific. Even with the considerable commercial investment in this area, it will take many years to build the cell-processing infrastructure to deliver this therapy to large numbers of patients outside major academic centres. CAR design and the choice of effector T cells need to be optimised to improve effectiveness and limit toxicities. CD19-CAR T-cell technology and clinical exploration continues apace. In future, multi-specific CARs could be used to avoid tumour escape. Incorporation of suicide genes or use of CARs whose activity can be tuned by administration of small-molecule pharmaceuticals might allow control of adverse events. T cells could be engineered to have enhanced persistence or to be resistant to hostile microenvironments. Likewise, the optimum position of CAR T-cell therapy in relation

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to existing therapies—whether CAR T cells are best employed in frank relapse or to deepen remission, whether as a bridge to transplant or a standalone treatment—needs to be defined. Such questions can only be answered in larger, well designed studies in defined patient cohorts. More broadly, while drawing attention to the potential of CAR T-cell therapy, CD19 is a unique and ideal target antigen, and whether suitable targets can be identified to extend this approach to other cancers remains to be seen. Nonetheless, this approach is without question the most significant therapeutic advance in acute lymphoblastic leukaemia for a generation, and might represent the beginning of a new era of engineered T cells for cancer therapy. *Persis J Amrolia, Martin Pule University College London Institute of Child Health, London WC1N 1EH, UK (PJA); and University College London Cancer Institute, London, UK (MP) [email protected] We declare no competing interests. 1

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Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 2014; published online Oct 13. http://dx.doi.org/10.1016/S01406736(14)61403-3. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365: 725–33. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3: 95ra73. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5: 177ra38. Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 2010; 116: 3875–86. Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived CD19targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 2013; 122: 4129–39. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 2014; published online Aug 25. DOI:10.1200/JCO.2014.56.2025. Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 2011; 121: 1822–26. Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer 2013; 13: 525–41. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014; 6: 224ra25. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509–18.

www.thelancet.com Published online October 13, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61729-3

Chimeric antigen receptor T cells for ALL.

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