Zuzana Tothova, MD, PhD, and David P. Steensma, MD
Drs. Tothova and Steensma indicated no relevant conflicts of interest.
Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509-1518.
Cancer is, fundamentally, a state of immunologic failure – the unfortunate result of the inability of a patient’s endogenous immune system to recognize and eliminate neoplastic clones. The latest and most promising tool in the long history of attempts to overcome inappropriate immunologic tolerance and harness the power of the immune system to eliminate cancer cells are bioengineered T cells, which are genetically manipulated to express chimeric antigen receptors (CARs) directed at tumor-associated antigens. These carefully designed recombinant receptors combine a cell-surface binding site targeting an antigen, which does not need peptide processing or HLA-assisted presentation, as well as a number of cytoplasmic signaling domains designed to enhance T-cell activation.
Since their initial development in the late 1980s, CAR T cells have undergone modifications in order to enhance both their anti-tumor activity and their persistence in vivo. The figure below depicts the evolution of CD19-specific CARs through three different generations, with the addition of co-stimulatory domains in later generations to augment anti-tumor activity. As it turns out, “the devil is in the details” with respect to these constructs, and changes in the CAR structure can dramatically alter both clinical effectiveness and adverse event profile.
In the summer of 2011, Carl June and his colleagues at the University of Pennsylvania reported the first successful use of second-generation, CD19-specific CARs in the treatment of a patient with relapsed chronic lymphocytic leukemia.1 A single low-dose infusion of autologous CAR-modified T cells resulted in stable engraftment and 1,000-fold expansion of tumor-specific T cells in vivo, and also resulted in complete disease remission with manageable chronic B-cell lymphopenia and hypogammaglobulinemia. A number of other patients have since been treated successfully using this strategy.
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The same group recently reported similar results in patients with relapsed or refractory B-cell acute lymphocytic leukemia (ALL) – a disease that continues to be extremely challenging to treat effectively in spite of increased use of allogeneic stem cell transplantation and availability of novel agents such as the anti-CD22 antibody-calicheamicin drug conjugate inotuzumab, and the CD3-CD19 bi-specific antibody blinatumomab. Grupp and his colleagues at the University of Pennsylvania used a self-inactivating lentiviral vector to introduce a second-generation CAR targeting CD19 antigen into autologous T cells harvested from two children with relapsed, refractory ALL. The authors were able to showthat CD19-CAR T cells expanded in the peripheral blood and bone marrow about 1,000-fold over their original engraftment levels, and their levels peaked at around day 10 after treatment. Both children achieved complete remission, but one patient relapsed with CD19-negative disease about two months after treatment. Deep sequencing of peripheral blood and marrow at IgH and TCRb loci documented molecular remission in one of the patients, with the absence of any detectable tumor cells by day 23. In contrast, the second patient was never able to clear her tumor clone as assessed by sequencing, in spite of morphologic remission. Similar results have been obtained by Renier Brentjens and his colleagues in New York using an alternative version of second-generation CD19-CAR T cells (Figure).2
CAR-modified T cells are not benign; severe adverse events have been observed by all groups working with these cells and seem to correlate with the dose of the cells administered. Adverse effects reported in the study by Grupp and colleagues included acute respiratory distress syndrome, febrile neutropenia, hypotension, encephalopathy, hepatic transaminitis, and macrophage activation syndrome. In one patient, a life-threatening inflammatory response resolved following administration of anti-cytokine therapy (specifically, etanercept and tocilizumab) and corticosteroids. Other CAR T-cell constructs have had slightly different toxicity profiles, including seizures.
Use of CAR T cells is likely to be practice-changing, not only in the realm of lymphoid malignancies, but also for other neoplasms. Studies are currently underway using this strategy in the treatment of plasma cell neoplasms and solid tumors, including neuroblastoma and several sarcomas. The applicability to myeloid malignancies is less straightforward, since a CAR T-cell response against most of the antigens present on malignant myeloid cells would result in severe, long-lasting neutropenia. Many questions remain with respect to CAR T-cell use in lymphoid neoplasms, such as the best and safest method of introducing CAR into T cells, the ideal number and type of costimulatory domains and specificity of scFv (Figure) for maximal anti-tumor effect, the optimal conditioning chemotherapy protocol for lymphoreduction and dose of cells to be infused, and how best to manage post-infusion cytokine storm without compromising the odds of long-term remission or cure.
This study provides exciting evidence that CD19-specific CAR T cells can induce long-lasting remission in patients with aggressive CD19+ pre-B ALL. Additional studies will be needed to determine the long-term safety and efficacy profile, how this approach will compare with the use of the new ALL antibodies, and which patients have the most potential to benefit from this novel treatment.
1. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-733.
2. 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.
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