Multi-Specific CAR Targeting to Prevent Antigen Escape
Purpose of Review
Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable remission induction rates for relapsed/refractory B cell malignancies. However, loss of the CAR-targeted antigen, known as antigen escape, accounts for a substantial percentage of relapses following CAR therapy and is a major barrier to durable remission. Here, we discuss mechanisms for antigen escape and strategies to prevent this pattern of relapse, including the use of multi-specific CARs, which recognize and target multiple tumor-associated antigens simultaneously.
Preclinical and early clinical trial data indicates that multi-specific CAR therapy for B cell malignancies is both safe and effective. Optimal combinations of target antigens, as well as different multi-specific CAR formats, are currently being evaluated.
Although still in early stages of development, multi-specific CAR therapy represents a promising approach to mitigate antigen loss–related relapses and improve durability of remission in patients with refractory B cell malignancies, and may be applicable to other types of cancer.
KeywordsCAR T cell Antigen loss Antigen escape Multi-specific Bivalent Lineage switch
Compliance with Ethical Standards
Conflict of Interest
Zachary Walsh, Savannah Ross, and Terry J. Fry declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 4.Qin H, Ramakrishna S, Nguyen S, Fountaine TJ, Ponduri A, Stetler-Stevenson M, et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol Ther - Oncolytics. 2018;11:127–37 Available from: http://www.sciencedirect.com/science/article/pii/S2372770518300305. Accessed 11 April 2019.CrossRefGoogle Scholar
- 5.•• Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20–8. Demonstrated efficacy of CD22-treated CAR for B-ALL and impact of antigen density on CAR functionality. CrossRefGoogle Scholar
- 6.Ramakrishna S, Highfill SL, Walsh Z, Nguyen SM, Lei H, Shern JF, et al. Modulation of target antigen density improves CAR T cell functionality and persistence. Clin Cancer Res. 2019:clincanres.3784.2018 Available from: http://clincancerres.aacrjournals.org/content/early/2019/05/18/1078-0432.CCR-18-3784.abstract. Accessed 22 May 2019.
- 8.Qin H, Nguyen SM, Ramakrishna S, Tarun S, Yang L, Verdini NP, et al. Novel CD19/CD22 bicistronic chimeric antigen receptors outperform single or bivalent cars in eradicating CD19<sup>+</sup>CD22<sup>+</sup>, CD19<sup>-</sup>, and CD22<sup>-</sup> pre-B leukemia. Blood. 2017;130(Suppl 1):810 LP–810.Google Scholar
- 14.Bagashev A, Sotillo E, Tang C-HA, Black KL, Perazzelli J, Seeholzer SH, et al. CD19 Alterations Emerging after CD19-Directed Immunotherapy Cause Retention of the Misfolded Protein in the Endoplasmic Reticulum. Mol Cell Biol. 2018;38(21).Google Scholar
- 15.Yates B, Shalabi H, Salem D, Delbrook C, Yuan CM, Stetler-Stevenson M, et al. Sequential CD22 targeting impacts CD22 CAR-T cell response. Blood. 2018;132(Suppl 1):282 LP–282 Available from: http://www.bloodjournal.org/content/132/Suppl_1/282.abstract Accessed 22 May 2019.CrossRefGoogle Scholar
- 17.Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, Qin 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
- 20.Park JH, Geyer MB. Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood. 2016;127(26):3312 LP–3320 Available from: http://www.bloodjournal.org/content/127/26/3312.abstract. Accessed 11 April 2019.CrossRefGoogle Scholar
- 22.Majzner RG, Rietberg SP, Labanieh L, Sotillo E, Weber EW, Lynn RC, et al. Low CD19 antigen density diminishes efficacy of CD19 CAR T cells and can be overcome by rational redesign of CAR signaling domains. Blood. 2018. 132(Suppl 1):963 LP – 963963. Available from: http://www.bloodjournal.org/content/132/Suppl_1/963.abstract. Accessed 16 April 2019.
- 26.Gardner R, Annesley C, Finney O, Summers C, Lamble AJ, Rivers J, et al. Early clinical experience of CD19 x CD22 dual specific CAR T cells for enhanced anti-leukemic targeting of acute lymphoblastic leukemia. Blood. 2018;132(Suppl 1):278 LP–278 Available from: http://www.bloodjournal.org/content/132/Suppl_1/278.abstract. Accessed 11 April 2019.CrossRefGoogle Scholar
- 28.Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape find the latest version: tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest. 2016;126(8):3036–52.CrossRefGoogle Scholar
- 29.Zah E, Lin M-Y, Silva-Benedict A, Jensen MC, Chen YY. T Cells Expressing CD19/CD20 Bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res. 2016;4(6):498 LP–508 Available from: http://cancerimmunolres.aacrjournals.org/content/4/6/498.abstract. Accessed 11 April 2019.CrossRefGoogle Scholar
- 30.Amrolia PJ, Wynn R, Hough R, Vora A, Bonney D, Veys 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(Suppl 1):279 LP–279 Available from: http://www.bloodjournal.org/content/132/Suppl_1/279.abstract Accessed 16 April 2019.CrossRefGoogle Scholar
- 31.• Ardeshna K, Marzolini MAV, Osborne W, Al-Hajj M, Thomas S, Faulkner J, et al. Study of AUTO3, the first bicistronic chimeric antigen receptor (CAR) targeting CD19 and CD22, followed by Anti-PD1 consolidation in patients with relapsed/refractory (r/r) diffuse large B cell lymphoma (DLBCL): Alexander study. Blood. 2018;132(Suppl 1):1679 LP–1679 Available from: http://www.bloodjournal.org/content/132/Suppl_1/1679.abstract. Accessed 16 April 2019. Clinical trial demonstrating early efficacy of bicistronic CARs targeting CD19 and CD22 for the treatment of r/r leukemia CrossRefGoogle Scholar
- 32.• Schultz LM, Davis KL, Baggott C, Chaudry C, Marcy AC, Mavroukakis 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(Suppl 1):898 LP–898 Available from: http://www.bloodjournal.org/content/132/Suppl_1/898.abstract. Accessed 16 April 2019. Clinical trial demonstrating early efficacy of bivalent CARs targeting CD19 and CD22 for the treatment of pediatric and young adult B-ALL.CrossRefGoogle Scholar
- 33.Hossain N, Sahaf B, Abramian M, Spiegel JY, Kong K, Kim S, et al. Phase I experience with a bi-specific CAR targeting CD19 and CD22 in adults with B-cell malignancies. Blood. 2018;132(Suppl 1):490 LP–490 Available from: http://www.bloodjournal.org/content/132/Suppl_1/490.abstract.CrossRefGoogle Scholar
- 34.Shah NN, Zhu F, Taylor C, Schneider D, Krueger W, Worden A, 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(Suppl 1):4193 LP–4193 Available from: http://www.bloodjournal.org/content/132/Suppl_1/4193.abstract.CrossRefGoogle Scholar
- 35.Li D, Hu Y, Jin Z, Zhai Y, Tan Y, Sun Y, et al. TanCAR T cells targeting CD19 and CD133 efficiently eliminate MLL leukemic cells. Leukemia. 2018;32(9):2012–6. https://doi.org/10.1038/s41375-018-0212-z,2018.
- 36.De Munter S, Ingels J, Goetgeluk G, Bonte S, Pille M, Weening K, et al. Nanobody Based Dual Specific CARs. Int J Mol Sci. 2018;19(2).Google Scholar
- 39.Qin H, Cho M, Haso W, Zhang L, Tasian SK, Oo HZ, et al. Eradication of B-ALL using chimeric antigen receptor-expressing T cells targeting the TSLPR oncoprotein. Blood. 2015;126(5):629–39.Google Scholar
- 40.Wang Y, Xu Y, Li S, Liu J, Xing Y, Xing H, et al. Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. J Hematol Oncol. 2018;11(1):60.Google Scholar
- 42.Fousek K, Watanabe J, George A, An X, Samaha H, Navai SA, et al. Targeting primary pre-B cell acute lymphoblastic leukemia and CD19-negative relapses using trivalent CAR T cells. Blood. 2017;130(Suppl 1):4614 LP–614 Available from: http://www.bloodjournal.org/content/130/Suppl_1/4614.abstract.Google Scholar
- 43.Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology. 2018;20(4):506–18.Google Scholar