Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies
Abstract
:1. Introduction
2. The Role of CD19 CAR T-Cell Therapy in B-Cell Malignancies
3. Cancer Cell Killing Mechanisms by CAR T-Cells
4. Antigen-Positive Relapse after CD19 CAR T-Cell Therapy
5. Antigen-Negative Relapse
6. CAR-Driven Acquired CD19 Mutations
7. Alternative Splicing of CD19
8. Masking of CD19 Epitope
9. Low Antigen Density
10. Lineage Switching
11. Treatment Strategy to Prevent Antigen-Positive Relapse
12. Overcoming Resistance to CAR T-Cell Therapy
13. Dual and Tandem CARs against Antigen Loss
14. Armored CAR T-Cells to Improve Antitumor Immunity
15. Universal CAR T-Cell Approaches
16. Conclusions
Funding
Conflicts of Interest
References
- Eshhar, Z. The T-body approach: Redirecting T cells with antibody specificity. Handb. Exp. Pharmacol. 2008, 181, 329–342. [Google Scholar]
- Curran, K.J.; Pegram, H.J.; Brentjens, R.J. Chimeric antigen receptors for T cell immunotherapy: Current understanding and future directions. J. Gene Med. 2012, 14, 405–415. [Google Scholar] [CrossRef] [PubMed]
- Dai, H.; Wang, Y.; Lu, X.; Han, W. Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy. J. Natl. Cancer Inst. 2016, 108, djv439. [Google Scholar] [CrossRef] [PubMed]
- Davila, M.L.; Riviere, I.; Wang, X.; Bartido, S.; Park, J.; Curran, K.; Chung, S.S.; Stefanski, J.; Borquez-Ojeda, O.; Olszewska, M.; 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. [Google Scholar] [CrossRef] [PubMed]
- Kochenderfer, J.N.; Dudley, M.E.; Kassim, S.H.; Somerville, R.P.; Carpenter, R.O.; Stetler-Stevenson, M.; Yang, J.C.; Phan, G.Q.; Hughes, M.S.; Sherry, R.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. [Google Scholar] [CrossRef]
- Kalos, M.; Levine, B.L.; Porter, D.L.; Katz, S.; Grupp, S.A.; Bagg, A.; June, C.H. 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. [Google Scholar] [CrossRef]
- Cai, B.; Guo, M.; Wang, Y.; Zhang, Y.; Yang, J.; Guo, Y.; Dai, H.; Yu, C.; Sun, Q.; Qiao, J.; et al. Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. J. Hematol. Oncol. 2016, 9, 131. [Google Scholar] [CrossRef]
- Zhang, W.Y.; Wang, Y.; Guo, Y.L.; Dai, H.R.; Yang, Q.M.; Zhang, Y.J.; Zhang, Y.; Chen, M.X.; Wang, C.M.; Feng, K.C.; et al. Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: An early phase IIa trial report. Signal Transduct. Target. Ther. 2016, 1, 16002. [Google Scholar] [CrossRef]
- Wang, C.M.; Wu, Z.Q.; Wang, Y.; Guo, Y.L.; Dai, H.R.; Wang, X.H.; Li, X.; Zhang, Y.J.; Zhang, W.Y.; Chen, M.X.; et al. Autologous T Cells Expressing CD30 Chimeric Antigen Receptors for Relapsed or Refractory Hodgkin Lymphoma: An Open-Label Phase I Trial. Clin. Cancer Res. 2017, 23, 1156–1166. [Google Scholar] [CrossRef]
- Maude, S.L.; Frey, N.; Shaw, P.A.; Aplenc, R.; Barrett, D.M.; Bunin, N.J.; Chew, A.; Gonzalez, V.E.; Zheng, Z.; Lacey, S.F.; et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 2014, 371, 1507–1517. [Google Scholar] [CrossRef]
- Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef] [PubMed]
- Lee, D.W.; Kochenderfer, J.N.; Stetler-Stevenson, M.; Cui, Y.K.; Delbrook, C.; Feldman, S.A.; Fry, T.J.; Orentas, R.; Sabatino, M.; Shah, N.N.; 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. [Google Scholar] [CrossRef]
- Gardner, R.; Wu, D.; Cherian, S.; Fang, M.; Hanafi, L.A.; Finney, O.; Smithers, H.; Jensen, M.C.; Riddell, S.R.; Maloney, D.G.; et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 2016, 127, 2406–2410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, J.H.; Rivière, I.; Gonen, M.; Wang, X.; Sénéchal, B.; Curran, K.J.; Sauter, C.; Wang, Y.; Santomasso, B.; Mead, E.; et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 449–459. [Google Scholar] [CrossRef] [PubMed]
- Turtle, C.J.; Hanafi, L.A.; Berger, C.; Gooley, T.A.; Cherian, S.; Hudecek, M.; Sommermeyer, D.; Melville, K.; Pender, B.; Budiarto, T.M.; et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Investig. 2016, 126, 2123–2138. [Google Scholar] [CrossRef]
- Neelapu, S.S.; Locke, F.L.; Bartlett, N.L.; Lekakis, L.J.; Miklos, D.B.; Jacobson, C.A.; Braunschweig, I.; Oluwole, O.O.; Siddiqi, T.; Lin, Y.; et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 2017, 377, 2531–2544. [Google Scholar] [CrossRef] [PubMed]
- Schuster, S.J.; Bishop, M.R.; Tam, C.S.; Waller, E.K.; Borchmann, P.; McGuirk, J.P.; Jäger, U.; Jaglowski, S.; Andreadis, C.; Westin, J.R.; et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N. Engl. J. Med. 2019, 380, 45–56. [Google Scholar] [CrossRef]
- Jacobson, C.A.; Hunter, B.; Armand, P.; Kamihara, Y.; Ritz, J.; Rodig, S.J.; Wright, K.; Lipschitz, M.; Redd, R.A.; Maus, M.V.; et al. Axicabtagene Ciloleucel in the Real World: Outcomes and Predictors of Response, Resistance and Toxicity. Blood 2018, 132, 92. [Google Scholar]
- Oak, J.; Spiegel, J.Y.; Sahaf, B.; Natkunam, Y.; Long, S.R.; Hossain, N.; Mackall, C.L.; Kong, K.A.; Miklos, D.B. Target Antigen Downregulation and Other Mechanisms of Failure after Axicabtagene Ciloleucel (CAR19) Therapy. Blood 2018, 132, 4656. [Google Scholar]
- O’Connell, J.; O’Sullivan, G.C.; Collins, J.K.; Shanahan, F. The Fas Counterattack: Fas-Mediated T Cell Killing by Colon Cancer Cells Expressing Fas Ligand. J. Exp. Med. 1996, 184, 1075–1082. [Google Scholar] [CrossRef]
- Peter, M.E.; Hadji, A.; Murmann, A.E.; Brockway, S.; Putzbach, W.; Pattanayak, A.; Ceppi, P. The Role of CD95 and CD95 Ligand in Cancer. Cell Death Differ. 2015, 22, 885–886. [Google Scholar] [CrossRef] [PubMed]
- Kagi, D.; Vignaux, F.; Ledermann, B.; Borki, K.; Depraetere, V.; Nagata, S.; Hengartner, H. Fas and Perforin Pathways as Major Mechanisms of T cell-mediated cytotoxicity. Science 1994, 265, 528–530. [Google Scholar] [CrossRef] [PubMed]
- Lowin, B.; Hahne, M.; Mattmann, C.; Tschopp, J. Cytolytic T-Cell Cytotoxicity Is Mediated through Perforin and Fas Lytic Pathways. Nature 1994, 370, 650–652. [Google Scholar] [CrossRef] [PubMed]
- Martínez-Lostao, L.; Anel, A.; Pardo, J. How Do Cytotoxic Lymphocytes Kill Cancer Cells? Clin. Cancer Res. 2015, 21, 5047–5056. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Walczak, H. Death Receptor-Ligand Systems in Cancer, Cell Death, and Inflammation. Cold Spring Harb. Perspect. Biol. 2013, 5, a008698. [Google Scholar] [CrossRef] [PubMed]
- Nagata, S.; Tanaka, M. Programmed Cell Death and the Immune System. Nat. Rev. Immunol. 2017, 17, 333–340. [Google Scholar] [CrossRef] [PubMed]
- Waring, P.; Mullbacher, A. Cell Death Induced by the Fas/Fas Ligand Pathway and Its Role in Pathology. Immunol. Cell Biol. 1999, 77, 312–317. [Google Scholar] [CrossRef] [PubMed]
- Hong, L.K.; Chen, Y.; Smith, C.C.; Montgomery, S.A.; Vincent, B.G.; Dotti, G.; Savoldo, B. CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30-Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions. Cancer Immunol. Res. 2018, 6, 1274–1287. [Google Scholar] [CrossRef]
- Hung, K.; Hayashi, R.; Lafond-Walker, A.; Lowenstein, C.; Pardoll, D.; Levitsky, H. The Central Role of CD4+ T Cells in the Antitumor Immune Response. J. Exp. Med. 1998, 188, 2357–2368. [Google Scholar] [CrossRef] [Green Version]
- Tatsumi, T.; Huang, J.; Gooding, W.E.; Gambotto, A.; Robbins, P.D.; Vujanovic, N.L.; Alber, S.M.; Watkins, S.C.; Okada, H.; Storkus, W.J. Intratumoral Delivery of Dendritic Cells Engineered to Secrete Both Interleukin (IL)-12 and IL-18 Effectively Treats Local and Distant Disease in Association with Broadly Reactive Tc1-Type Immunity. Cancer Res. 2003, 63, 6378–6386. [Google Scholar]
- Pegram, H.J.; Lee, J.C.; Hayman, E.G.; Imperato, G.H.; Tedder, T.F.; Sadelain, M.; Brentjens, R.J. Tumor-Targeted T Cells Modified to Secrete IL-12 Eradicate Systemic Tumors without Need for Prior Conditioning. Blood 2012, 119, 4133–4141. [Google Scholar] [CrossRef] [PubMed]
- Cullen, S.P.; Martin, S.J. Mechanisms of Granule-Dependent Killing. Cell Death Differ. 2008, 15, 251–262. [Google Scholar] [CrossRef] [PubMed]
- De Saint Basile, G.; Ménasché, G.; Fischer, A. Molecular Mechanisms of Biogenesis and Exocytosis of Cytotoxic Granules. Nat. Rev. Immunol. 2010, 10, 568–579. [Google Scholar] [CrossRef] [PubMed]
- Otero, D.C.; Anzelon, A.N.; Rickert, R.C. CD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals. J. Immunol. 2003, 170, 73–83. [Google Scholar] [CrossRef] [PubMed]
- Otero, D.C.; Rickert, R.C. CD19 function in early and late B cell development. II. CD19 facilitates the pro-B/pre-B transition. J. Immunol. 2003, 171, 5921–5930. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Brooks, S.R.; Li, X.; Anzelon, A.N.; Rickert, R.C.; Carter, R.H. The physiologic role of CD19 cytoplasmic tyrosines. Immunity 2002, 17, 501–514. [Google Scholar] [CrossRef]
- Kotani, H.L.; Li, G.; Yao, J.; Mesa, T.E.; Chen, J.; Boucher, J.C.; Yoder, S.J.; Zhou, J.; Davila, M.L. Aged CAR T Cells Exhibit Enhanced Cytotoxicity and Effector Function but Shorter Persistence and Less Memory-like Phenotypes. Blood 2018, 132, 2047. [Google Scholar]
- Gardner, R.; Finney, O.; Brakke, H.; Rhea, S.; Hicks, R.; Doolittle, D.; Lopez, M.; Orentas, R.J.; Li, D.; Jensen, M.C. Starting T Cell and Cell Product Phenotype Are Associated with Durable Remission of Leukemia Following CD19 CAR-T Cell Immunotherapy. Blood 2018, 132, 4022. [Google Scholar]
- Fesnak, A.D.; June, C.H.; Levine, B.L. Engineered T cells: The promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 2016, 16, 566–581. [Google Scholar] [CrossRef]
- Yasukawa, M.; Ohminami, H.; Arai, J.; Kasahara, Y.; Ishida, Y.; Fujita, S. Granule Exocytosis, and Not the Fas/Fas Ligand System, is the Main Pathway of Cytotoxicity Mediated by Alloantigen-Specific CD4(+) as well as CD8(+) Cytotoxic T Lymphocytes in Humans. Blood 2000, 95, 2352–2355. [Google Scholar]
- Hombach, A.; Köhler, H.; Rappl, G.; Abken, H. Human CD4+ T Cells Lyse Target Cells via Granzyme/Perforin upon Circumvention of MHC Class II Restriction by an Antibody-like Immunoreceptor. J. Immunol. 2006, 177, 5668–5675. [Google Scholar] [CrossRef] [PubMed]
- Liadi, I.; Singh, H.; Romain, G.; Rey-Villamizar, N.; Merouane, A.; Adolacion, J.R.; Kebriaei, P.; Huls, H.; Qiu, P.; Roysam, B.; et al. Individual Motile CD4+ T Cells Can Participate in Efficient Multikilling through Conjugation to Multiple Tumor Cells. Cancer Immunol. Res. 2015, 3, 473–482. [Google Scholar] [CrossRef] [PubMed]
- Shah, N.N.; Fry, T. Mechanisms of resistance to CAR T cell therapy. Nat. Rev. Clin. Oncol. 2019, 16, 372–385. [Google Scholar] [CrossRef] [PubMed]
- Long, A.H.; Haso, W.M.; Shern, J.F.; Wanhainen, K.M.; Murgai, M.; Ingaramo, M.; Smith, J.P.; Walker, A.J.; Kohler, M.E.; Venkateshwara, V.R.; et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 2015, 21, 581–590. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zheng, S.; Asnani, M.; Thomas-Tikhonenko, A. Escape from ALL-CARTaz: Leukemia Immunoediting in the Age of Chimeric Antigen Receptors. Cancer J. 2019, 25, 217–222. [Google Scholar] [CrossRef] [PubMed]
- Sotillo, E.; Barrett, D.M.; Black, K.L.; Bagashev, A.; Oldridge, D.; Wu, G.; Sussman, R.; Lanauze, C.; Ruella, M.; Gazzara, M.R.; et al. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015, 5, 1282–1295. [Google Scholar] [CrossRef] [PubMed]
- Orlando, E.J.; Han, X.; Tribouley, C.; Wood, P.A.; Leary, R.J.; Riester, M.; Levine, J.E.; Qayed, M.; Grupp, S.A.; Boyer, M.; et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 2018, 24, 1504–1506. [Google Scholar] [CrossRef] [PubMed]
- Wang, B.D.; Lee, N.H. Aberrant RNA Splicing in Cancer and Drug Resistance. Cancers 2018, 10, 458. [Google Scholar] [CrossRef] [PubMed]
- Rexer, B.N.; Arteaga, C.L. Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications. Crit. Rev. Oncog. 2012, 17, 1–16. [Google Scholar] [CrossRef] [Green Version]
- Mitra, D.; Brumlik, M.J.; Okamgba, S.U.; Zhu, Y.; Duplessis, T.T.; Parvani, J.G.; Lesko, S.M.; Brogi, E.; Jones, F.E. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol. Cancer Ther. 2009, 8, 2152–2162. [Google Scholar] [CrossRef] [Green Version]
- Poulikakos, P.; Persaud, Y.; Janakiraman, M.; Kong, X.; Ng, C.; Moriceau, G.; Shi, H.; Atefi, M.; Titz, B.; Gabay, M.T.; et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011, 480, 387–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shi, H.; Hugo, W.; Kong, X.; Hong, A.; Koya, R.C.; Moriceau, G.; Chodon, T.; Guo, R.; Johnson, D.B.; Dahlman, K.B.; et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014, 4, 80–93. [Google Scholar] [CrossRef] [PubMed]
- Malcovati, L.; Papaemmanuil, E.; Bowen, D.T.; Boultwood, J.; Della Porta, M.G.; Pascutto, C.; Travaglino, E.; Groves, M.J.; Godfrey, A.L.; Ambaglio, I.; et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasm. Blood 2011, 118, 6239–6246. [Google Scholar] [CrossRef] [PubMed]
- Thol, F.; Kade, S.; Schlarmann, C.; Löffeld, P.; Morgan, M.; Krauter, J.; Wlodarski, M.W.; Kölking, B.; Wichmann, M.; Görlich, K.; et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 2012, 119, 3578–3584. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Makishima, H.; Visconte, V.; Sakaguchi, H.; Jankowska, A.M.; Abu Kar, S.; Jerez, A.; Przychodzen, B.; Bupathi, M.; Guinta, K.; Afable, M.G.; et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012, 119, 3203–3210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ruella, M.; Xu, J.; Barrett, D.M.; Fraietta, J.A.; Reich, T.J.; Ambrose, D.E.; Klichinsky, M.; Shestova, O.; Patel, P.R.; Kulikovskaya, I.; et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat. Med. 2018, 24, 1499–1503. [Google Scholar] [CrossRef] [PubMed]
- Davenport, A.J.; Cross, R.S.; Watson, K.A.; Liao, Y.; Shi, W.; Prince, H.M.; Beavis, P.A.; Trapani, J.A.; Kershaw, M.H.; Ritchie, D.S.; et al. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc. Natl. Acad. Sci. USA 2018, 115, E2068–E2076. [Google Scholar] [CrossRef] [Green Version]
- Walker, A.J.; Majzner, R.G.; Zhang, L.; Wanhainen, K.; Long, A.H.; Nguyen, S.M.; Lopomo, P.; Vigny, M.; Fry, T.J.; Orentas, R.J.; et al. Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase. Mol. Ther. 2017, 25, 2189–2201. [Google Scholar] [CrossRef] [Green Version]
- Hombach, A.A.; Görgens, A.; Chmielewski, M.; Murke, F.; Kimpel, J.; Giebel, B.; Abken, H. Superior Therapeutic Index in Lymphoma Therapy: CD30(+) CD34(+) Hematopoietic Stem Cells Resist a Chimeric Antigen Receptor T-cell Attack. Mol. Ther. 2016, 24, 1423–1434. [Google Scholar] [CrossRef]
- Watanabe, K.; Terakura, S.; Martens, A.C.; van Meerten, T.; Uchiyama, S.; Imai, M.; Sakemura, R.; Goto, T.; Hanajiri, R.; Imahashi, N.; et al. Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8+ T cells. J. Immunol. 2015, 194, 911–920. [Google Scholar] [CrossRef]
- Park, J.H.; Geyer, M.B.; Brentjens, R.J. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: Interpreting clinical outcomes to date. Blood 2016, 127, 3312–3320. [Google Scholar] [CrossRef] [PubMed]
- Turtle, C.J.; Riddell, S.R. Artificial antigen-presenting cells for use in adoptive immunotherapy. Cancer J. 2010, 16, 374–381. [Google Scholar] [CrossRef] [PubMed]
- Blaeschke, F.; Stenger, D.; Kaeuferle, T.; Willier, S.; Lotfi, R.; Kaiser, A.D.; Assenmacher, M.; Döring, M.; Feucht, J.; Feuchtinger, T. Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia. Cancer Immunol. Immunother. 2018, 67, 1053–1066. [Google Scholar] [CrossRef] [PubMed]
- Fraietta, J.A.; Lacey, S.F.; Orlando, E.J.; Pruteanu-Malinici, I.; Gohil, M.; Lundh, S.; Boesteanu, A.C.; Wang, Y.; O’Connor, R.S.; Hwang, W.T.; et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 2018, 24, 563–571. [Google Scholar] [CrossRef]
- Corrigan-Curay, J.; Kiem, H.P.; Baltimore, D.; O’Reilly, M.; Brentjens, R.J.; Cooper, L.; Forman, S.; Gottschalk, S.; Greenberg, P.; Junghans, R.; et al. T-cell immunotherapy: Looking forward. Mol. Ther. 2014, 22, 1564–1574. [Google Scholar] [CrossRef]
- Gattinoni, L.; Finkelstein, S.E.; Klebanoff, C.A.; Antony, P.A.; Palmer, D.C.; Spiess, P.J.; Hwang, L.N.; Yu, Z.; Wrzesinski, C.; Heimann, D.M.; et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 2005, 202, 907–912. [Google Scholar] [CrossRef] [PubMed]
- Turtle, C.J.; Berger, C.; Sommermeyer, D.; Hanafi, L.A.; Pender, B.; Robinson, E.M.; Melville, K.; Budiarto, T.M.; Steevens, N.N.; Chaney, C.; et al. Anti-CD19 Chimeric Antigen Receptor-Modified T Cell Therapy for B Cell Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Fludarabine and Cyclophosphamide Lymphodepletion Improves in Vivo Expansion and Persistence of CAR-T Cells and Clinical Outcomes. Blood 2015, 126, 184. [Google Scholar]
- Turtle, C.J.; Hanafi, L.A.; Berger, C.; Sommermeyer, D.; Pender, B.; Robinson, E.M.; Melville, K.; Budiarto, T.M.; Steevens, N.N.; Chaney, C.; et al. Addition of Fludarabine to Cyclophosphamide Lymphodepletion Improves in Vivo Expansion of CD19 Chimeric Antigen Receptor-Modified T Cells and Clinical Outcome in Adults with B Cell Acute Lymphoblastic Leukemia. Blood 2015, 126, 3773. [Google Scholar]
- Fraietta, J.A.; Beckwith, K.A.; Patel, P.R.; Ruella, M.; Zheng, Z.; Barrett, D.M.; Lacey, S.F.; Melenhorst, J.J.; McGettigan, S.E.; Cook, D.R.; et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 2016, 127, 1117–1127. [Google Scholar] [CrossRef] [Green Version]
- Ruella, M.; Kenderian, S.S.; Shestova, O.; Fraietta, J.A.; Qayyum, S.; Zhang, Q.; Maus, M.V.; Liu, X.; Nunez-Cruz, S.; Klichinsky, M.; et al. The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma. Clin. Cancer Res. 2016, 22, 2684–2696. [Google Scholar] [CrossRef] [Green Version]
- Mullowney, M.W.; McClure, R.A.; Robey, M.T.; Kelleher, N.L.; Thomson, R.J. Natural products from thioester reductase containing biosynthetic pathways. Nat. Prod. Rep. 2018, 35, 847–878. [Google Scholar] [CrossRef] [PubMed]
- Zolov, S.N.; Rietberg, S.P.; Bonifant, C.L. Programmed cell death protein 1 activation preferentially inhibits CD28 CAR-T cells. Cytotherapy 2018, 20, 1259–1266. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Zhang, Y.; Cheng, C.; Cheng, A.W.; Zhang, X.; Li, N.; Xia, C.; Wei, X.; Liu, X.; Wang, H. CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res. 2017, 27, 154–157. [Google Scholar] [CrossRef] [PubMed]
- Hui, E.; Cheung, J.; Zhu, J.; Su, X.; Taylor, M.J.; Wallweber, H.A.; Sasmal, D.K.; Huang, J.; Kim, J.M.; Mellman, I.; et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 2017, 355, 1428–1433. [Google Scholar] [CrossRef] [PubMed]
- Gardner, R.A.; Finney, O.; Annesley, C.; Brakke, H.; Summers, C.; Leger, K.; Bleakley, M.; Brown, C.; Mgebroff, S.; Kelly-Spratt, K.S.; et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 2017, 129, 3322–3331. [Google Scholar] [PubMed]
- Fry, T.J.; Shah, N.N.; Orentas, R.J.; Stetler-Stevenson, M.; Yuan, C.M.; Ramakrishna, S.; Wolters, P.; Martin, S.; Delbrook, C.; Yates, B.; et al. CD22-targeted CAR T cells induce remission in B-ALL that is I or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 2018, 24, 20–28. [Google Scholar] [CrossRef] [PubMed]
- Ramakrishna, S.; Highfill, S.L.; Walsh, Z.; Nguyen, S.M.; Lei, H.; Shern, J.F.; Qin, H.; Kraft, I.L.; Stetler-Stevenson, M.; Yuan, C.M.; et al. Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence. Clin. Cancer Res. 2019. [Google Scholar] [CrossRef]
- Majzner, R.G.; Mackall, C.L. Tumor Antigen Escape from CAR T-cell Therapy. Cancer Discov. 2018, 8, 1219–1226. [Google Scholar] [CrossRef] [Green Version]
- Rossi, J.G.; Bernasconi, A.R.; Alonso, C.N.; Rubio, P.L.; Gallego, M.S.; Carrara, C.A.; Guitter, M.R.; Eberle, S.E.; Cocce, M.; Zubizarreta, P.A.; et al. Lineage switch in childhood acute leukemia: An unusual event with poor outcome. Am. J. Hematol. 2012, 87, 890–897. [Google Scholar] [CrossRef]
- Rayes, A.; McMasters, R.L.; O’Brien, M.M. Lineage Switch in MLL-Rearranged Infant Leukemia Following CD19-Directed Therapy. Pediatr. Blood Cancer 2016, 63, 1113–1115. [Google Scholar] [CrossRef]
- Jacoby, E.; Nguyen, S.M.; Fountaine, T.J.; Welp, K.; Gryder, B.; Qin, H.; Yang, Y.; Chien, C.D.; Seif, A.E.; Lei, H.; et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat. Commun. 2016, 7, 12320. [Google Scholar] [CrossRef] [PubMed]
- Evans, A.G.; Rothberg, P.G.; Burack, W.R.; Huntington, S.F.; Porter, D.L.; Friedberg, J.W.; Liesveld, J.L. Evolution to plasmablastic lymphoma evades CD19-directed chimeric antigen receptor T cells. Br. J. Haematol. 2015, 171, 205–209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ruella, M.; Barrett, D.M.; Kenderian, S.S.; Shestova, O.; Hofmann, T.J.; Perazzelli, J.; Klichinsky, M.; Aikawa, V.; Nazimuddin, F.; Kozlowski, M.; et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Investig. 2016, 126, 3814–3826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guedan, S.; Calderon, H.; Posey, A.D., Jr.; Maus, M.V. Engineering and Design of Chimeric Antigen Receptors. Mol. Ther. Methods Clin. Dev. 2018, 12, 145–156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Amrolia, P.J.; Wynn, R.; Hough, R.; Vora, A.; Bonney, D.; Veys, P.; Rao, K.; Chiesa, R.; Al-Hajj, M.; Cordoba, S.P.; et al. Simultaneous Targeting of CD19 and CD22: Phase I Study of AUTO3, a Bicistronic Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Pediatric Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL): Amelia Study. Blood 2018, 132, 279. [Google Scholar]
- Schultz, L.M.; Davis, K.L.; Baggott, C.; Chaudry, C.; Marcy, A.C.; Mavroukakis, S.; Sahaf, B.; Kong, K.A.; Muffly, L.S.; Kim, S.; et al. Phase 1 Study of CD19/CD22 Bispecific Chimeric Antigen Receptor (CAR) Therapy in Children and Young Adults with B Cell Acute Lymphoblastic Leukemia (ALL). Blood 2018, 132, 898. [Google Scholar]
- Grada, Z.; Hegde, M.; Byrd, T.; Shaffer, D.R.; Ghazi, A.; Brawley, V.S.; Corder, A.; Schönfeld, K.; Koch, J.; Dotti, G.; et al. TanCAR: A Novel Bispecific Chimeric Antigen Receptor for Cancer Immunotherapy. Mol. Ther. Nucleic Acids. 2013, 2, e105. [Google Scholar] [CrossRef]
- Hegde, M.; Mukherjee, M.; Grada, Z.; Pignata, A.; Landi, D.; Navai, S.A.; Wakefield, A.; Fousek, K.; Bielamowicz, K.; Chow, K.K.; et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Investig. 2016, 126, 3036–3052. [Google Scholar] [CrossRef]
- Shah, N.N.; Zhu, F.; Taylor, C.; Schneider, D.; Krueger, W.; Worden, A.; Yim, S.; Fenske, T.S.; Hamadani, M.; Johnson, B.; et al. A Phase 1 Study with Point-of-Care Manufacturing of Dual Targeted, Tandem Anti-CD19, Anti-CD20 Chimeric Antigen Receptor Modified T (CAR-T) Cells for Relapsed, Refractory, Non-Hodgkin Lymphoma. Blood 2018, 132, 4193. [Google Scholar]
- Hegde, M.; Corder, A.; Chow, K.K.; Mukherjee, M.; Ashoori, A.; Kew, Y.; Zhang, Y.J.; Baskin, D.S.; Merchant, F.A.; Brawley, V.S.; et al. Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Mol. Ther. 2013, 21, 2087–2101. [Google Scholar] [CrossRef]
- Jaspers, J.E.; Brentjens, R.J. Development of CAR T cells designed to improve antitumor efficacy and safety. Pharmacol. Ther. 2017, 178, 83–91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kerkar, S.P.; Leonardi, A.J.; van Panhuys, N.; Zhang, L.; Yu, Z.; Crompton, J.G.; Pan, J.H.; Palmer, D.C.; Morgan, R.A.; Rosenberg, S.A.; et al. Collapse of the tumor stroma is triggered by IL-12 induction of Fas. Mol. Ther. 2013, 21, 1369–1377. [Google Scholar] [CrossRef] [PubMed]
- Armitage, R.J.; Fanslow, W.C.; Strockbine, L.; Sato, T.A.; Clifford, K.N.; Macduff, B.M.; Anderson, D.M.; Gimpel, S.D.; Davis-Smith, T.; Maliszewski, C.R.; et al. Molecular and biological characterization of a murine ligand for CD40. Nature 1992, 357, 80–82. [Google Scholar] [CrossRef] [PubMed]
- Schönbeck, U.; Libby, P. The CD40/CD154 receptor/ligand dyad. Cell Mol. Life Sci. 2001, 58, 4–43. [Google Scholar] [PubMed]
- Stephan, M.T.; Ponomarev, V.; Brentjens, R.J.; Chang, A.H.; Dobrenkov, K.V.; Heller, G.; Sadelain, M. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat. Med. 2007, 13, 1440–1449. [Google Scholar] [CrossRef] [PubMed]
- Van Herpen, C.M.; van der Laak, J.A.; de Vries, I.J.; van Krieken, J.H.; de Wilde, P.C.; Balvers, M.G.; Adema, G.J.; De Mulder, P.H. Intratumoral Recombinant Human Interleukin-12 Administration in Head and Neck Squamous Cell Carcinoma Patients Modifies Locoregional Lymph Node Architecture and Induces Natural Killer Cell Infiltration in the Primary Tumor. Clin. Cancer Res. 2005, 11, 1899–1909. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rosenberg, S.A.; Yang, J.C.; Sherry, R.M.; Kammula, U.S.; Hughes, M.S.; Phan, G.Q.; Citrin, D.E.; Restifo, N.P.; Robbins, P.F.; Wunderlich, J.R.; et al. Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T Cell Transfer Immunotherapy. Clin. Cancer Res. 2011, 17, 4550–4557. [Google Scholar] [CrossRef]
- Kerkar, S.; Rosenberg, S.; Restifo, N. IL-12 Triggers a Programmatic Change in Dysfunctional Myeloid-Derived Cells within Mouse Tumors. J. Clin. Investig. 2011, 121, 4746–4757. [Google Scholar] [CrossRef]
- Kerkar, S.; Muranski, P.; Kaiser, A.; Boni, A.; Sanchez-Perez, L.; Yu, Z.; Palmer, D.C.; Reger, R.N.; Borman, Z.A.; Zhang, L.; et al. Tumor-Specific CD8+T Cells Expressing Interleukin-12 Eradicate Established Cancers in Lymphodepleted Hosts. Cancer Res. 2010, 70, 6725–6734. [Google Scholar] [CrossRef]
- Zhao, J.; Lin, Q.; Song, Y.; Liu, D. Universal CARs, universal T cells, and universal CAR T cells. J. Hematol. Oncol. 2018, 11, 132. [Google Scholar] [CrossRef]
- Torikai, H.; Reik, A.; Liu, P.Q.; Zhou, Y.; Zhang, L.; Maiti, S.; Huls, H.; Miller, J.C.; Kebriaei, P.; Rabinovich, B.; et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 2012, 119, 5697–5705. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Torikai, H.; Reik, A.; Soldner, F.; Warren, E.H.; Yuen, C.; Zhou, Y.; Crossland, D.L.; Huls, H.; Littman, N.; Zhang, Z.; et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 2013, 122, 1341–1349. [Google Scholar] [CrossRef] [PubMed]
- Poirot, L.; Philip, B.; Schiffer-Mannioui, C.; Le Clerre, D.; Chion-Sotinel, I.; Derniame, S.; Potrel, P.; Bas, C.; Lemaire, L.; Galetto, R.; et al. Multiplex Genome-Edited T-cell Manufacturing Platform for “Off-the-shelf” Adoptive T-cell Immunotherapies. Cancer Res. 2015, 75, 3853–3864. [Google Scholar] [CrossRef] [PubMed]
- Georgiadis, C.; Preece, R.; Nickolay, L.; Etuk, A.; Petrova, A.; Ladon, D.; Danyi, A.; Humphryes-Kirilov, N.; Ajetunmobi, A.; Kim, D.; et al. Long Terminal Repeat CRISPR-CAR-Coupled “Universal” T Cells Mediate Potent Anti-leukemic Effects. Mol. Ther. 2018, 26, 1215–1227. [Google Scholar] [CrossRef] [PubMed]
- Knott, G.J.; Doudna, J.A. CRISPR-Cas guides the future of genetic engineering. Science 2018, 361, 866–869. [Google Scholar] [CrossRef] [Green Version]
- Cho, J.H.; Collins, J.J.; Wong, W.W. Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses. Cell 2018, 173, 1426–1438.e11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Study | Patients (n) | Co-stimulatory Domain | Lymphodepletion Regimen | Response Rate | Relapsed or not Responded Rate | CD19 (-) Relapse Rate (%) | Reference |
---|---|---|---|---|---|---|---|
B-ALL | |||||||
CHOP (Maude et al.) | Pediatric and adult B-ALL (30) | 4-1BB | Investigator’s choice | CR, 27 of 30 (90%) | 8 of 27 (29.6%) | 3 of 27 (11.1%) | [10] |
ELIANA (Maude et al.) | Pediatric and young Adult B-ALL (75) | 4-1BB | Flu-Cy/Cytarabine-etopo | CR, 61 of 75 (81%) | 17 of 61 (27.9%) | 15 of 61 (24.6%) | [11] |
NCI (Lee et al.) | Pediatric and adult B-ALL (21) | CD28 | Flu-Cy/FLAG/Ifosfamide-etopo | CR, 14 of 21 (66.7%) | 7 of 14 (50%) | 2 of 14 (14.3%) | [12] |
SCRI (Gardner el al.) | Pediatric and adult B-ALL (7) | 4-1BB | Flu-Cy/Cy only | CR, 100% | 2 of 7 (28.6%) | 2 of 7 (28.6%), lineage-witch | [13] |
MSKCC (Park et al.) | Adult B-ALL (53) | CD28 | Flu-Cy/Cy only | CR, 44 of 53 (83%) | 25 of 44 (57%) | 4 of 44 (9%) | [14] |
FHCRC (Turtle et al.) | Adult B-ALL (29) | 4-1BB | Flu-Cy/Cy only | CR, 27 of 29 (93%) | 9 of 27 (33.3%) | 2 of 27 (7.4%) | [15] |
B-NHL | |||||||
ZUMA-1 (Neelapu et al.) | DLBCL, PMBCL, tFL (111) | CD28 | Flu-Cy | ORR, 82 % (CR, 54%) | 52 of 111 (46.8%) | 3 of 11 analyzed (27.2%) | [16] |
Schuster et al. | DLBCL, FL (28) | 4-1BB | Investigator’s choice | ORR, 52 % (CR, 40%) | 5 of 28 (17.9%) | 1 of 5 analyzed, (20%) | [17] |
Jacobson et al. | Aggressive B-NHL (73) | CD28 | unknown | ORR, 57 % (CR, 36%) | Unknown | 1 of 4 analyzed, (25%) | [18] |
Oak et al. | DLBCL, PMBCL, tFL (22) | CD28 | unknown | ORR, 86 % (CR, 45.5%) | 5 (22.7%) | 2 of 4 analyzed, (50%) | [19] |
CAR Type | Characteristics | References |
---|---|---|
Dual targeted CAR T-cell therapy | ||
Dual CAR | Dual CARs consist of two separate second-generation CARs targeting two different tumor antigens. The dual CARs can be classified in “bi-cistronic CAR” type expressing two CARs such as CD19 and CD22 simultaneously and “mono-CAR” type expressing the two CARs separately. | [83,84,85,86] |
Tandem CAR | A single CAR molecule is incorporated into two different binding molecules with different antigen specificities. | [61,87,88,89,90] |
Armored CAR | ||
CAR T-cells with mechanisms to allow for local delivery of cytokine to enhance antitumor activity of T cells but to reduce activities of immune suppressor cells and mitigate potential toxicity. TRUCKs: T-cells redirected for universal cytokine-mediated killing -CAR T-cells lead to release IL-12 upon engagement with cancer -leads to recruitment of activated macrophages, inflammation, and cancer cell lysis with antigen loss. | [31,91,92,93,94,95,96,97,98,99] | |
Universal CAR | ||
In several genome editing techniques (ZFN, TALEN, and CRISPR/Cas9) to modify gene and re-engineer cells, universal CAR could be knocked out TCR and HLA. The optimal universal CAR might be HLA and TCR negative and include non-classical HLA to avoid NK cell lysis. SUPRA CAR: consists of zipCAR linked to B leucine zipper and zipFv linked to A leucine zipper. Through binding between A and B leucine zippers, any extracellular signal linked to the A leucine zip can activate the T-cells. | [100,101,102,103,104,105,106] |
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Song, M.-K.; Park, B.-B.; Uhm, J.-E. Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies. Int. J. Mol. Sci. 2019, 20, 5010. https://doi.org/10.3390/ijms20205010
Song M-K, Park B-B, Uhm J-E. Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies. International Journal of Molecular Sciences. 2019; 20(20):5010. https://doi.org/10.3390/ijms20205010
Chicago/Turabian StyleSong, Moo-Kon, Byeong-Bae Park, and Ji-Eun Uhm. 2019. "Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies" International Journal of Molecular Sciences 20, no. 20: 5010. https://doi.org/10.3390/ijms20205010