Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

Nature Communications - Tập 11 Số 1
Eugenia Zah1, Eunwoo Nam1, Vinya Bhuvan1, Uyen Tran2, Brenda Ji1, Stanley B. Gosliner1, Xiuli Wang3, Christine E. Brown3, Yvonne Y. Chen4
1Department of Chemical and Biomolecular Engineering, University of California–Los Angeles, 420 Westwood Plaza, BH 5513, Los Angeles, CA, USA
2Department of Chemistry and Biochemistry, University of California–Los Angeles, 420 Westwood Plaza, BH 5513, Los Angeles, CA, USA
3Department of Hematology and Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope Beckman Research Institute and Medical Center, 1500 E. Duarte Rd., Duarte, CA, USA
4Department of Microbiology, Immunology, and Molecular Genetics, University of California–Los Angeles, 420 Westwood Plaza, BH 5513, Los Angeles, CA, USA

Tóm tắt

AbstractChimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit superior CAR expression and function compared to T cells that co-express individual BCMA and CS1 CARs. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, while CAR-T cell treatment alone achieves durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

Từ khóa


Tài liệu tham khảo

Cancer Facts and Figures 2019, American Cancer Society (2019). https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf.

Cowan, A. J. et al. Global burden of multiple myeloma. JAMA Oncol. 98121, 1221–1227 (2018).

Moreau, P., Attal, M. & Facon, T. Frontline therapy of multiple myeloma. Blood 125, 3076–3085 (2015).

Ali, S. A. et al. T cells expressing an anti-B cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128, 1688–1701 (2016).

Brudno, J. et al. T cells genetically modified to express an anti-B cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36, 2267–2280 (2018).

Berdeja, J. G. et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: Updated results from a multicenter study of bb2121 anti-Bcma CAR T cell therapy. Blood 130, 740 (2017).

Cohen, A. D. et al. Safety and efficacy of B cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood 130, 505 (2017).

Smith, E. L. et al. Development and evaluation of a human single chain variable fragment (scFv) derived Bcma rargeted CAR T cell vector leads to a high objective response rate in patients with advanced MM. Blood 130, 742 (2017).

Grada, Z. et al. TanCAR: A novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol. Ther. Nucleic Acids 2, e105 (2013).

Zah, E., Lin, M.-Y., Silva-Benedict, A., Jensen, M. C. & Chen, Y. Y. T cells expressing CD19/CD20 bi-specific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. https://doi.org/10.1158/2326-6066.CIR-15-0231 (2016).

Hegde, M. et al. Tandem CAR T cells targeting HER2 and IL13R α 2 mitigate tumor antigen escape. J. Clin. Invest. 126, 3036–3052 (2016).

Qin, H. et al. Novel CD19/CD22 Bicistronic chimeric antigen receptors outperform single or bivalent CARs in eradicating CD19+CD22+, CD19−, and CD22− Pre-B Leukemia. Am. Soc. Hematol. 130, 810 (2017).

Lee, L. et al. An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma. Blood 131, 746–758 (2018).

Novak, A. J. et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 103, 689–694 (2004).

Moreaux, J. et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 106, 1021–1030 (2005).

Lee, L. et al. Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma. Br. J. Haematol. 174, 911–922 (2016).

Hsi, E. D. et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin. Cancer Res. 14, 2775–2784 (2008).

Tai, Y.-T. et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces aritibody-dependent cellular cytotoxicity in the bone marrow mitieu. Blood 112, 1329–1337 (2008).

Wang, X. et al. Lenalidomide enhances the function of CS1 chimeric antigen receptor-redirected T cells against multiple myeloma. Clin. Cancer Res. 24, 106–119 (2018).

Hudecek, M. et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19, 3153–3164 (2013).

Hudecek, M. et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol. Res. 3, 125–135 (2015).

James, J. R. & Vale, R. D. Biophysical mechanism of T-cell receptor triggering in a reconstituted system. Nature 487, 64–69 (2012).

Williams, M., Tso, Y., Landolfi, N. F., Powers, D. B. & Liu, G. Therapeutic use of anti-CS1 antibodies US (US Patents, 2010). https://patents.google.com/patent/US7709610B2/en.

Chen, K. H. et al. A compound chimeric antigen receptor strategy for targeting multiple myeloma. Leukemia 32, 402–412 (2018).

Bouchon, A., Cella, M., Grierson, H. L., Cohen, J. I. & Colonna, M. Cutting edge: activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J. Immunol. 167, 5517–5521 (2001).

Turtle, C. J. et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 1, 1–16 (2016).

Berger, C. et al. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J. Clin. Invest. 118, 294–305 (2008).

Sommermeyer, D. et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30, 492–500 (2016).

Xu, Y. et al. Closely-related T-memory stem cells correlate with in-vivo expansion of CAR.CD19-T cells in patients and are preserved by IL-7 and IL-15. Blood 123, 3750–3759 (2014).

Frigault, M. J. et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol. Res. 3, 356–367 (2015).

Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

Verma, V. et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance. Nat. Immunol. 20, 1231–1243 (2019).

Zelba, H. et al. Accurate quantification of T-cells expressing PD-1 in patients on anti-PD-1 immunotherapy. Cancer Immunol. Immunother. 67, 1845–1851 (2018).

Rosenzweig, M. et al. Preclinical data support leveraging CS1 chimeric antigen receptor T-cell therapy for systemic light chain amyloidosis. Cytotherapy 19, 861–866 (2017).

Lonial, S. et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl. J. Med. 373, 621–631 (2015).

Magen, H. & Muchtar, E. Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment. Ther. Adv. Hematol. 7, 187–195 (2016).

Zonder, J. A. et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 120, 552–559 (2013).

Kumar, M., Keller, B., Makalou, N. & Sutton, R. E. Systematic determination of the packaging limit of lentiviral vectors. Hum. Gene Ther. 12, 1893–1905 (2001).

Bos, T. J., De Bruyne, E., Van Lint, S., Heirman, C. & Vanderkerken, K. Large double copy vectors are functional but show a size-dependent decline in transduction efficiency. J. Biotechnol. 150, 37–40 (2010).

Qin, H., Haso, W., Nguyen, S. M. & Fry, T. J. Preclinical development of bispecific chimeric antigen receptor targeting both CD19 and CD22. Blood 126, 4427 (2015).

Gibson, D. G. et al. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat. Methods 6, 343–345 (2009).

Brogdon, J. et al. WO2016014565_Treatment of cancer using humanized anti-BCMA CAR.pdf. (US Patents, 2016). https://patents.google.com/patent/WO2016014565A2/en.

Carpenter, R. O. et al. B cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19, 2048–2060 (2013).

Oden, F. et al. Potent anti-tumor response by targeting. Mol. Oncol. 9, 1348–1358 (2015).

Lee, L. S. H. et al. An APRIL based chimeric antigen receptor to simultaneously target BCMA and TACI in multiple myeloma (MM) has potent activity in vitro and in vivo. Blood 128, 379 (2016).

Chu, J. et al. Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells. Clin. Cancer Res. 20, 3989–4000 (2014).

Yu, J., Hofmeister, C. & Chu, J. WO2014179759_CS1 CAR.pdf. (US Patents, 2014). https://patents.google.com/patent/US20160075784A1/en.

Wang, X. et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118, 1255–1263 (2011).

Thông tin
Thông tin xuất bản

Nature Communications

Tập 11 Số 1

Thông tin tác giả