Cell and Gene Therapy

We are developing both CAR-T and bispecific antibody therapies to target acute myeloid leukemia (AML), multiple myeloma (MM), B cell non-Hodgkin lymphoma (B-NHL), B cell acute lymphocytic leukemia (B-ALL), T cell acute lymphocytic leukemia (T-ALL) as well as related solid tumors. We are using genetic and expression analysis of primary patient tumor samples to identify novel protein targets.

(Dr. Julie O’Neal, Dr. Miriam Kim, Dr. Ramzi Abboud, Dr. Parmeshwar Amatya, Julie Ritchey, Dr. Jingyu (Jerry) Xiang, Julia Wang, Omar Ibrahim, Susan Gladney)

 
DrawImpacts_Animation_orange3_web.gif
arrow3Grey.png
 

We have multiple programs to address some of the challenges of CAR-T therapy.

 

To address antigen escape, where the  tumor cells adapt so they become CAR-T resistant, we are engineering CARs that target two antigens simultaneously. We are testing the ability of multiple cytokines to enhance in vivo expansion and persistence of CAR-T cells, and therefore efficacy. For problematic cancers whose target antigens are also on the effector cell (e.g., T cell malignancies) we use CRISPR to eliminate the antigen in the immune effector cells prior to introducing the CARs to prevent fratricide.

Most CAR-T therapy is used in the autologous setting due to the risk of GvHD. We and others eliminate this potential by using gene edited CAR-T cells that can be expanded and theoretically made available off-the-shelf to any patient with a particular cancer type, which reduces time to treatment, cost, and eliminates risk of production failure. We are investigating the use of an alternative immune cell type: the invariant natural killer T cell (iNKT). Since these cells do not cause GvHD, we are exploring their potential as a “universal” source of immune effector cells.

We also develop bispecific antibodies to target tumor antigens.  Bispecific antibodies have the advantage of being immediately available for patient treatment, without the need for complex manufacturing. Some of these reagents and strategies are being advanced into clinical studies here at the Siteman Cancer Center at Washington University and are being manufactured in our GMP facility. 

Both CAR- and bispecific antibody-based immunotherapies can induce cytokine release syndrome (CRS), which can result in considerable morbidity and mortality for patients.  We have developed in vitro and in vivo CRS models to understand the mechanism behind CRS, and investigate strategies to prevent or overcome it.

We also collaborate with other academic or industry partners to assess potential treatments for CRS or proprietary immunotherapeutics, some of which we manufacture onsite.

 

 Key Publications

  • Eissenberg LG, Rettig MP, Ritchey JK, Prior JL, Schwarz SW, Frye J, White BS, Fulton RS, Ghobadi A, Cooper ML, Couriel DR, Seeulam ME, Piwnica-Worms D, Dehdashti F, Cornetta K, and DiPersio J. [(18)F]FBG PET/CT Imaging of CD34-TK75 Transduced Donor Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility. Mol Ther Jun;23(6):1110-22;2015. doi: 10.1038/mt.2015.48. Epub 2015 Mar 25. PMID: 25807290.

  • Al Hussani M, Rettig MP, Ritchey JK, Karpova D, Uy GL, Eissenberg LG, Gao F, Eades , WC, Bonvini E, Chichili GR, Moore Pa, Jonson S, Collins L, and DiPersio JF. Targeting CD123 in AML using a T-cell directed dual-affinity re-targeting (DART®) platform. Blood 2016 Jan 7;127(1):122-31. doi: 10.1182/blood 2014-05-575704 (epub 2015 Nov 3) PMID: 26531164.

  • Cooper ML, Choi J, Staser K, Ritchey JK, Devenport JM, Eckardt K, Rettig MP, Wang B, Eissenberg LG, Ghobadi A, Gehrs LN, Prior JL, Achilefu S, Miller CA, Fronick CC, O’Neal J, Gao F, Weinstock DM, Gutierrez A, Fulton RS, and DiPersio JF. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 2018 Sep;32(9):1970-1983. doi: 10.1038/s41375-018-0065-5. Epub 2018 Feb 20. PMID: 29483708.

  • Cooper ML, DiPersio JF. Chimeric Antigen Receptor T Cells (CAR-T) for the Treatment of T Cell Malignancies. Best Pract Res Clin Haematol 2019 Dec;32(4):101097.

  • Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H, Sullivan AH, Viboch EJ, Patel T, Ibrahimova N, Warren SE, Arruda A, Liang Y, Smith TH, Foulds GA, Bailey MD, Gowen-MacDonald J, Muth J, Schmitz M, Cesano A, Pockley AG, Valk PJM, Lowenberg B, Bornhauser M, Tasian SK, Rettig MP, Davidson-Moncada JK, DiPersio JF, Rutella S. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Transl Med 2020 June 3;12(546):eaaz0463. doi: 10.1126/scitranslmed.aaz0463. PMID: 32493790.

  • Cancilla D, Rettig MP, DiPersio JF. Targeting CXCR4 in AML and ALL. Front Oncol 2020 Sep 4;10:1672. doi: 10.3389/fonc.2020.01672. eCollection 20.20. PMID: 33014834.

  • Gang M, Marin ND, Wong P, Neal CC, Marsala L, Foster M, Schappe T, Meng W, Tran J, Schaettler M, Davila M, Gao F, Cashen AF, Bartlett NL, Mehta-Shah N, Kahl BS, Kim MY, Cooper ML, DiPersio JF, Berrien-Elliott MM, Fehniger TA. CAR-Modified Memory- Like NK Cells Exhibit Potent Responses to NK-Resistant Lymphomas. Blood 2020 Nov 12;136(20):2308-2318.

  • Ghai A, Zheleznyak A, Mixdorf M, O'Neal J, Ritchey J, Rettig M, DiPersio J, Shokeen M, Achilefu S.  Development of [(89)Zr]DFO-Elotuzumab for ImmunoPET Imaging of CS1 in Multiple Myeloma. Eur J Nucl Med Mol Imaging 2021 May;48(5):1302-1311.

  • Kim MY, Cooper ML, Jacobs MT, Ritchey JK, Hollaway J, Fehniger TA, DiPersio JF. CD7- Deleted Hematopoietic Stem Cells Can Restore Immunity After CAR T Cell Therapy. JCI Insight 2021 Aug 23;6(16):e149819.

  • Ghai A, Fettig N, Fontana F, DiPersio J, Rettig M, O'Neal J, Achilefu S, Shoghi KI, Shokeen M.  In Vivo Quantitative Assessment of Therapeutic Response to Bortezomib Therapy in Disseminated Animal Models of Multiple Myeloma With [(18)F]FDG and [(64)Cu]Cu-LLP2A PET. EJNMMI Res 2021 Sep 29;11(1):97:1186.

  • Hathi D, Chanswangphuwana C, Cho N, Fontana F, Maji D, Ritchey J, O'Neal J, Ghai A, Duncan K, Akers WJ, Fiala M, Vij R, DiPersio JF, Rettig M, Shokeen M.  Ablation of VLA4 in Multiple Myeloma Cells Redirects Tumor Spread and Prolongs Survival. Sci Rep 2022 Jan 7;12(1):30.

  • Alhallak K, Sun J, Muz B, Jeske A, O'Neal J, Ritchey JK, Achilefu S, DiPersio JF, Azab AK. Liposomal Phytohemagglutinin: In Vivo T-Cell Activator as a Novel Pan-Cancer Immunotherapy. J Cell Mol Med 2022 Feb;26(3):940-944.

  • Kim MY, Jayasinghe R, Devenport JM, Ritchey JK, Rettig MP, O'Neal J, Staser KW, Kennerly KM, Carter AJ, Gao F, Lee BH, Cooper ML, DiPersio JF. A Long-Acting Interleukin-7, RhIL-7-HyFc, Enhances CAR T Cell Expansion, Persistence, and Anti-Tumor Activity. Nat Commun 2022 Jun 13;13(1):3296.

  • O'Neal J, Ritchey JK, Cooper ML, Niswonger J, Sofia Gonzalez L, Street E, Rettig MP, Gladney SW, Gehrs L, Abboud R, Prior JL, Haas GJ, Jayasinghe RG, Ding L, Ghobadi A, Vij R, DiPersio JF. CS1 CAR-T Targeting the Distal Domain of CS1 (SLAMF7)Shows Efficacy in High Tumor Burden Myeloma Model Despite Fratricide of CD8+CS1 Expressing CAR-T Cells. Leukemia 2022 Jun;36(6):1625-1634.

  • Yao L, Wang JT, Jayasinghe RG, O'Neal J, Tsai CF, Rettig MP, Song Y, Liu R, Zhao Y, Ibrahim OM, Fiala MA, Fortier JM, Chen S, Gehrs L, Rodrigues FM, Wendl MC, Kohnen D, Shinkle A, Cao S, Foltz SM, Zhou DC, Storrs E, Wyczalkowski MA, Mani S, Goldsmith SR, Zhu Y, Hamilton M, Liu T, Chen F, Vij R, Ding L, DiPersio JF.  Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma Cancer Res 2023 Apr 14;83(8):1214-1233.

  • O'Neal J, Cooper ML, Ritchey JK, Gladney SW, Niswonger J, Gonzalez LS, Street E, Haas GJ, Carter AJ, Amayta PN, Gao F, Lee BH, Choi D, Berrien-Elliott MM, Zhou AY, Fehniger TA, Rettig MP, DiPersio JF.  Anti-Myeloma Efficacy of CAR-INKT Is Enhanced With a Long-Acting IL-7, RhIL-7hyFc  Blood Adv 2023 Jul 3:bloodadvances2023010032; [ahead of print].

  • O’Neal, J., Ritchey, J. K., Cooper, M. L., Niswonger, J., Sofía González, L., Street, E., Rettig, M. P., Gladney, S. W., Gehrs, L., Abboud, R., Prior, J. L., Haas, G. J., Jayasinghe, R. G., Ding, L., Ghobadi, A., Vij, R. & DiPersio, J. F. CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells Jun 2022, In: Leukemia.36, 6, p. 1625-1634 10 p.

  • Kim, M. Y., Jayasinghe, R., Devenport, J. M., Ritchey, J. K., Rettig, M. P., O’Neal, J., Staser, K. W., Kennerly, K. M., Carter, A. J., Gao, F., Lee, B. H., Cooper, M. L. & DiPersio, J. F. A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity, Dec 2022, In: Nature communications. 13, 1, 3296.

  • Yao, L., Wang, J. T., Jayasinghe, R. G., O’Neal, J., Tsai, C. F., Rettig, M. P., Song, Y., Liu, R., Zhao, Y., Ibrahim, O. M., Fiala, M. A., Fortier, J. M., Chen, S., Gehrs, L., Rodrigues, F. M., Wendl, M. C., Kohnen, D., Shinkle, A., Cao, S. & Foltz, S. M. & 12 others. Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma, Apr 15 2023, In: Cancer research. 83, 8, p. 1214-1233 20 p.

  • Rimando, J. C., Chendamarai, E., Rettig, M. P., Jayasinghe, R., Christopher, M. J., Ritchey, J. K., Christ, S., Kim, M. Y., Bonvini, E. & DiPersio, J. F. Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells, Apr 6 2023, In: Blood. 141, 14, p. 1718-1723 6 p.

  • Xiang, J., Devenport, J. M., Carter, A. J., Staser, K. W., Kim, M. Y., O’ Neal, J., Ritchey, J. K., Rettig, M. P., Gao, F., Rettig, G., Turk, R., Lee, B. H., Cooper, M. L. & DiPersio, J. F. An “off-the-shelf” CD2 universal CAR-T therapy for T-cell malignancies, Dec 2023, In: Leukemia. 37, 12, p. 2448-2456 9 p.

  • O’Neal, J., Cooper, M. L., Ritchey, J. K., Gladney, S., Niswonger, J., González, L. S., Street, E., Haas, G. J., Carter, A., Amayta, P. N., Gao, F., Lee, B. H., Choi, D., Berrien-Elliott, M., Zhou, A., Fehniger, T. A., Rettig, M. P. & DiPersio, J. F. Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7-hyFc,  Oct 24 2023, In: Blood Advances. 7, 20, p. 6009-6022 14 p.

  • Eissenberg, L. G., Ritchey, J. K., Rettig, M. P., Patel, D. A., Vij, K., Gao, F., Smith, V., Han, T. H. & DiPersio, J. F. Control of acute myeloid leukemia and generation of immune memory in vivo using AMV564, a bivalent bispecific CD33 x CD3 T cell engager May 2024, In: PloS one. 19, 5 MAY, e0300174.

    Meeting Presentations: 

  • CGC (Cancer Genomics Consortium) 13th Annual Meeting, July 31- August 3, 2022

  • Sunday, July 31, 2022, Pre-meeting workshops, Session 3 (5:15 - 5:45 PM): The Dual PI3K Inhibitor Duvelisib Potently Inhibits Cytokine Release Syndrome while Maintaining CAR-T Function, Parmeshwar Amatya, Washington University School of Medicine.