Antigen-specific and precision immunotherapy for autoimmune diseases

Curative treatment approaches for autoimmune and rheumatic diseases do currently not exist. Current treatment strategies for rheumatic disease rely on broadly acting immunosuppressive drugs that reduce self-reactive immune responses but also impair protective immunity, resulting in infection, poor vaccine responses, and treatment-related morbidity. In addition, available therapies often lack desired potency to control disease and therapeutic responses are not predictable.

Ideal treatments for autoimmune diseases would eliminate only the self-reactive immune cells that cause harm but preserve normal immune responses. Our goal is to develop personalized and antigen-specific immunotherapies that can achieve that, using orthogonal novel technologies and engineering platforms developed in our lab.

Chimeric antigen receptor (CAR)-T cell therapies targeting B cells have revolutionized the treatment of blood cancers over the past decade and can be curative. These emerging therapies can also achieve drug-free disease remission in patients with severe autoimmune and rheumatic diseases. However, CAR-T cell therapies indiscriminately deplete entire B cell compartments, leaving patients at least transiently at risk of infectious complications.

Our lab is developing multiple technologies that can overcome this limitation, pairing the unprecedented potency of T cell therapies with therapeutic precision. Our group developed a novel technology, CRISPR/Cas-engineered chimeric autoantigen-T cell receptor (CATCR)-T cells, to reprogram a patient's T cells so they can selectively target self-reactive immune cells while preserving normal immune populations. If successful, these therapies will transform the health of patients living with autoimmune and rheumatic disease by introducing new drugs that can control autoimmunity without increasing the risk of infection. We are advancing CATCR-T cells for various organ-specific and systemic autoimmune diseases, while working on off-the-shelf solutions that allow to advance precision immunotherapies at scale.

We believe that antigen-specific immunotherapies have the potential to offer curative treatment options for many patients suffering from systemic and organ-specific autoimmune diseases, shaping the future of rheumatology.

Collaborators

Bert Vogelstein, M.D.; Ludwig Center for Cancer Genetics and Therapeutics

Kenneth Kinzler, Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Shibin Zhou, M.D., Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Suman Paul, M.B.B.S., Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Nickolas Papadopoulos, Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Chetan Bettegowda, M.D., Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Drew Pardoll, M.D., Ph.D.; Bloomberg~Kimmel Institute for Cancer Immunotherapy

Michelle Petri, M.D., M.P.H.; Division of Rheumatology, The Johns Hopkins University

Antony Rosen, M.B.Ch.B., M.S.; Division of Rheumatology, The Johns Hopkins University

Recent Publications

• Falde SD, Fussner LA, Tazelaar HD, O'Brien EK, Lamprecht P, Konig MF, Specks U. Proteinase 3-specific antineutrophil cytoplasmic antibody-associated vasculitis. Lancet Rheumatol. 2024 Mar 28:S2665-9913(24)00035-3. doi: 10.1016/S2665-9913(24)00035-3.

• Nichakawade TD, Ge J, Mog BJ, Lee BS, Pearlman AH, Hwang MS, DiNapoli SR, Wyhs N, Marcou N, Glavaris S, Konig MF, Gabelli SB, Watson E, Sterling C, Wagner-Johnston N, Rozati S, Swinnen L, Fuchs E, Pardoll DM, Gabrielson K, Papadopoulos N, Bettegowda C, Kinzler KW, Zhou S, Sur S, Vogelstein B, Paul S. TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers. Nature. 2024 Mar 27. doi: 10.1038/s41586-024-07233-2.

• Konig MF. The rise of precision cellular therapies. Nat Rev Rheumatol. 2024 Jan 8;. doi: 10.1038/s41584-023-01073-6.

• Mog B, Shaw E, Hwang M, Pearlman A, DiNapoli S, Paul S, Bettegowda C, Papadopoulos N, Gabelli S, Petri M, Rosen A, Zhou S, Kinzler K, Vogelstein B, Konig MF. Chimeric Autoantigen-T Cell Receptor (CATCR)-T Cell Therapies to Selectively Target Autoreactive B Cells [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). [presented in Plenary Session III, American College of Rheumatology Convergence 2022]

• Zou RS, Liu Y, Gaido OER, Konig MF, Mog BJ, Shen LL, Aviles-Vazquez F, Marin-Gonzalez A, Ha T. Improving the sensitivity of in vivo CRISPR off-target detection with DISCOVER-Seq. Nat Methods. 2023 Apr 6. doi: 10.1038/s41592-023-01840-z. PMID: 37024653.

• Konig MF*, Paul S. More on CD19-CAR T Cells in Systemic Lupus Erythematosus. N Engl J Med. 2021 Nov 4;385(19):e67.

• Hwang MS, Miller MS, Thirawatananond P, Douglass J, Wright KM, Hsiue EH, Mog BJ, Aytenfisu TY, Murphy MB, Aitana Azurmendi P, Skora AD, Pearlman AH, Paul S, DiNapoli SR, Konig MF, Bettegowda C, Pardoll DM, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Gabelli SB. Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens. Nat Commun. 2021 Sep 6;12(1):5271.

• Pearlman AH, Hwang M, Konig MF, Hsiue E, Douglass J, DiNapoli SR, Mog BJ, Bettegowda C, Pardoll DM, Gabelli SB, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Targeting public neoantigens for cancer immunotherapy. Nature Cancer. 2021 May; 2(5):487-497.

• Hwang MS, Mog BJ, Douglass J, Pearlman AH, Hsiue EH, Paul S, DiNapoli SR, Konig MF, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Vogelstein B, Zhou S, Kinzler KW. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proc Natl Acad Sci U S A. 2021 Mar 23;118(12).

• Paul S, Pearlman AH, Douglass J, Mog BJ, Hsiue EH, Hwang MS, DiNapoli SR, Konig MF, Brown PA, Wright KM, Sur S, Gabelli SB, Li Y, Ghiaur G, Pardoll DM, Papadopoulos N, Bettegowda C, Kinzler KW, Zhou S, Vogelstein B. TCR β chain-directed bispecific antibodies for the treatment of T cell cancers. Sci Transl Med. 2021 Mar 10;13(584):eabd3595.

• Hsiue EH, Wright KM, Douglass J, Hwang MS, Mog BJ, Pearlman AH, Paul S, DiNapoli SR, Konig MF, Wang Q, Schaefer A, Miller MS, Skora AD, Azurmendi PA, Murphy MB, Liu Q, Watson E, Li Y, Pardoll DM, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B, Gabelli SB, Zhou S. Targeting a neoantigen derived from a common TP53 mutation. Science. 2021 Mar 5;371(6533):eabc8697.

• Douglass J, Hsiue EH, Mog BJ, Hwang MS, DiNapoli SR, Pearlman AH, Miller MS, Wright KM, Azurmendi PA, Wang Q, Paul S, Schaefer A, Skora AD, Molin MD, Konig MF, Liu Q, Watson E, Li Y, Murphy MB, Pardoll DM, Bettegowda C, Papadopoulos N, Gabelli SB, Kinzler KW, Vogelstein B, Zhou S. Bispecific antibodies targeting mutant RAS neoantigens. Sci Immunol. 2021 Mar 1;6(57).