Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen
S Rafiq, T J Purdon, A F Daniyan, M Koneru, T Dao, C Liu, D A Scheinberg, R J Brentjens, S Rafiq, T J Purdon, A F Daniyan, M Koneru, T Dao, C Liu, D A Scheinberg, R J Brentjens
Abstract
CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This in vivo functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy.
Conflict of interest statement
CONFLICT OF INTEREST
RJB is a co-founder, stockholder and consultant for Juno Therapeutics Inc. DAS and TD are inventors of TCRm technology owned by MSKCC, licensed to Novartis.
Figures
References
- Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38.
- Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–1517.
- Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, 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. 2015;385:517–528.
- Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118:4817–4828.
- Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139.
- Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822–1826.
- Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, 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. 2015;33:540–549.
- Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, et al. Phase I studies of central-memory-derived CD19 CAR T cell therapy following autologous HSCT in patients with B-cell NHL. Blood. 2016;127:2980–2990.
- Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T cells forward. Nat Rev Clin Oncol. 2016;13:370–383.
- Sugiyama H. WT1 (Wilms’ tumor gene 1): biology and cancer immunotherapy. Jpn J Clin Oncol. 2010;40:377–387.
- Hohenstein P, Hastie ND. The many facets of the Wilms’ tumour gene, WT1. Hum Mol Genet. 2006;15:R196–R201.
- Morrison AA, Viney RL, Ladomery MR. The post-transcriptional roles of WT1, a multifunctional zinc-finger protein. Biochim Biophys Acta. 2008;1785:55–62.
- Davies R, Moore A, Schedl A, Bratt E, Miyahawa K, Ladomery M, et al. Multiple roles for the Wilms’ tumor suppressor, WT1. Cancer Res. 1999;59:1747s–1750s. discussion 51s.
- Di Stasi A, Jimenez AM, Minagawa K, Al-Obaidi M, Rezvani K. Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front Immunol. 2015;6:36.
- Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H, et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood. 1994;84:3071–3079.
- Ogawa H, Tamaki H, Ikegame K, Soma T, Kawakami M, Tsuboi A, et al. The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood. 2003;101:1698–1704.
- Dao T, Scheinberg DA. Peptide vaccines for myeloid leukaemias. Best Pract Res Clin Haematol. 2008;21:391–404.
- Maslak PG, Dao T, Krug LM, Chanel S, Korontsvit T, Zakhaleva V, et al. Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia. Blood. 2010;116:171–179.
- Krug LM, Dao T, Brown AB, Maslak P, Travis W, Bekele S, et al. WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. Cancer Immunol Immunother. 2010;59:1467–1479.
- Dao T, Yan S, Veomett N, Pankov D, Zhou L, Korontsvit T, et al. Targeting the intracellular WT1 oncogene product with a therapeutic human antibody. Sci Transl Med. 2013;5:176ra33.
- Veomett N, Dao T, Liu H, Xiang J, Pankov D, Dubrovsky L, et al. Therapeutic efficacy of an Fc-enhanced TCR-like antibody to the intracellular WT1 oncoprotein. Clin Cancer Res. 2014;20:4036–4046.
- Dubrovsky L, Pankov D, Brea EJ, Dao T, Scott A, Yan S, et al. A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias. Blood. 2014;123:3296–3304.
- Dao T, Pankov D, Scott A, Korontsvit T, Zakhaleva V, Xu Y, et al. Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1. Nat Biotechnol. 2015;33:1079–1086.
- Fraietta JA, Schwab RD, Maus MV. Improving therapy of chronic lymphocytic leukemia with chimeric antigen receptor T cells. Semin Oncol. 2016;43:291–299.
- Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF, Sadelain M, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood. 2012;119:4133–4141.
- Pegram HJ, Purdon TJ, van Leeuwen DG, Curran KJ, Giralt SA, Barker JN, et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia. 2015;29:415–422.
- Lasek W, Zagozdzon R, Jakobisiak M. Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother. 2014;63:419–435.
- Koneru M, Purdon TJ, Spriggs D, Koneru S, Brentjens RJ. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors. Oncoimmunology. 2015;4:e994446.
- Ghani K, Wang X, de Campos-Lima PO, Olszewska M, Kamen A, Riviere I, et al. Efficient human hematopoietic cell transduction using RD114- and GALV-pseudotyped retroviral vectors produced in suspension and serum-free media. Hum Gene Ther. 2009;20:966–974.
- Chekmasova AA, Rao TD, Nikhamin Y, Park KJ, Levine DA, Spriggs DR, et al. Successful eradication of established peritoneal ovarian tumors in SCID-Beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen. Clin Cancer Res. 2010;16:3594–3606.
- Brentjens RJ, Santos E, Nikhamin Y, Yeh R, Matsushita M, La Perle K, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res. 2007;13:5426–5435.
- Ferrone CR, Perales MA, Goldberg SM, Somberg CJ, Hirschhorn-Cymerman D, Gregor PD, et al. Adjuvanticity of plasmid DNA encoding cytokines fused to immunoglobulin Fc domains. Clin Cancer Res. 2006;12:5511–5519.
- Lund RJ, Loytomaki M, Naumanen T, Dixon C, Chen Z, Ahlfors H, et al. Genome-wide identification of novel genes involved in early Th1 and Th2 cell differentiation. J Immunol. 2007;178:3648–3660.
- Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol. 2003;21:713–758.
- Zhao Q, Ahmed M, Tassev DV, Hasan A, Kuo TY, Guo HF, et al. Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential. Leukemia. 2015;29:2238–2247.
- Oren R, Hod-Marco M, Haus-Cohen M, Thomas S, Blat D, Duvshani N, et al. Functional comparison of engineered T cells carrying a native TCR versus TCR-like antibody-based chimeric antigen receptors indicates affinity/avidity thresholds. J Immunol. 2014;193:5733–5743.
- Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21:581–590.
- Chmielewski M, Kopecky C, Hombach AA, Abken H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 2011;71:5697–5706.
- Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z, et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res. 2010;70:6725–6734.
- Chinnasamy D, Yu Z, Kerkar SP, Zhang L, Morgan RA, Restifo NP, et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin Cancer Res. 2012;18:1672–1683.
- Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013;36:133–151.
- Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550–4557.
- Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917–924.
- Chapuis AG, Ragnarsson GB, Nguyen HN, Chaney CN, Pufnock JS, Schmitt TM, et al. Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. Sci Transl Med. 2013;5:174ra27.
Source: PubMed