Abstract IA20: Updates on CAR T Cells
Authors: June Carl H. , Scholler John , Ruella Marco , Fraietta Joseph , Melenhorst J. Jos , Ren Jiangtao , Zhao Yangbing 
Published: February 2019

The emergence of immune-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with the pillars of chemotherapy, radiation, and targeted small-molecule compounds. Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering provides the field with a broadly expanded set of tools for programming immune cells. In this presentation, I will discuss how these tools could be used to design the next generation of smart T-cell precision therapeutics.

We have been exploring in preclinical models and clinical trials methods to synthetically enhance T-cell antitumor efficacy by transfer of genetically engineered T cells. Infusions of chimeric antigen receptor (CAR) T cells can result in remissions in patients with hematologic malignancies, but efficacy is often limited by the extent of expansion and persistence of engineered lymphocytes. In a patient with a delayed clinical response, we show that a complete and durable response to CAR T cell therapy resulted from a clonal expansion of a single CAR T cell. At the peak of the antitumor response, 94 percent of CD8+ CTL019 cells originated from a single clone in which proviral insertion disrupted the gene encoding the methylcytosine dioxygenase TET2. We conclude that loss of function of TET2 secondary to insertional mutagenesis promoted T-cell proliferation, and that the progeny of a single CAR T cell induced durable remission in refractory leukemia.

In solid tumors, we have observed antitumor activity in patients with ovarian cancer, pancreatic ductal adenocarcinoma, pleural mesothelioma, and glioblastoma following infusion of CAR T cells expressing scFv specific for mesothelin or EGFRvIII. However, this approach has not yet resulted in complete tumor eradication. Using genome-edited T cells, it may be possible to enhance and prolong the activity of T cells that have disrupted immune and metabolic checkpoints. In preclinical studies, we show that TCR-specific T cells have enhanced antitumor activity following disruption of TCR alpha and beta genes and the PD1 gene using CRISPR/Cas9. This approach is just entering a clinical trial. These findings provide insights into the immunobiology of effector T cells and demonstrate the potential of multiplexed CRISPR/Cas9 genome editing to synthetically enhance the efficacy of immunotherapy.

References:

1. Lim WA, June CH. The principles of engineering immune cells to treat cancer. Cell 2017;168(4):724-40.

2. Ruella M, Klichinsky M, Kenderian SS, et al. Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells. Cancer Discov 2017;Jun 2. pii: CD-16-0850. doi: 10.1158/2159-8290.CD-16-0850. [Epub ahead of print]

3. Maude S, Frey N, Shaw P, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371(16):1507-17.

4. Tanyi JL, Stashwick C, Plesa G, Morgan MA, Porter D, Maus MV, June CH. Possible compartmental cytokine release syndrome in a patient with recurrent ovarian cancer after treatment with mesothelin-targeted CAR-T cells. J Immunother 2017.

5. Beatty GL, Haas AR, Maus MV, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2014;2(2):112-20.

6. Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest 2016;126(10):3814-26.

7. Chong EA, Melenhorst JJ, Lacey SF, et al. PD-1 blockade modulates chimeric antigen receptor (CAR) modified T cells and induces tumor regression: Refueling the CAR. Blood 2016. doi: 10.1182/blood-2016-09-738245

8. Ren J, Liu X, Fang C, et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res 2016; Nov 4. 10.1158/1078-0432.ccr-16-1300. [Epub ahead of print].

9. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7.

10. O’Rourke DM, Nasrallah MP, Desai A, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9(399), pii: eaaa0984. doi: 10.1126/scitranslmed.aaa0984.

11. Sampson JH, Maus MV, June CH. Immunotherapy for brain tumors. J Clin Oncol 2017;35(21):2450-6.

Citation Format: Carl H. June, John Scholler, Marco Ruella, Joseph Fraietta, J. Jos Melenhorst, Jiangtao Ren, Yangbing Zhao. Updates on CAR T Cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA20.