Cancer immunotherapy has ushered in a new chapter in cancer therapeutics. However, cancer therapeutics are often associated with deleterious autoimmune phenomena (immune-related adverse events, irAEs). The immunopathogenesis of irAE and to which extent they resemble spontaneous autoimmunity are under scrutiny. Conversely, cellular immunotherapy is a potential treatment for autoimmune disorders. In this talk I will discuss the state-of-the-art of the Jing-Jang regarding autoimmunity as side-effect, but also potential target of immunotherapy.

We developed the first de novo miniproteins that precisely inhibit TNF receptor 1 (TNFR1), overcoming challenges seen with conventional antibody therapies. These miniproteins block pathogenic TNF-α signaling with picomolar affinity in vitro and in vivo, selectively targeting TNFR1 while preserving beneficial TNFR2 activity. This novel mechanism offers a precise therapeutic strategy for alleviating autoimmune diseases.

Current treatments for autoimmune diseases rely on systemic immunosuppressants, which increase susceptibility to infections and injury. There is a pressing need for targeted therapies that address disease mechanisms more precisely. Polymeric biomaterials offer a promising solution by enabling specific targeting and robust immunomodulation. This presentation explores biomaterial-based approaches in which antigens are co-delivered with immunomodulatory factors or synthetic immunomodulatory polymers. These materials provide a tunable strategy to enhance therapeutic efficacy while minimizing systemic effects. By leveraging biomaterials for targeted immunomodulation, this approach aims to address unmet needs in autoimmune disease treatment.

My lab focuses on pioneering strategies to treat inflammatory and autoimmune diseases by fostering antigen- and/or tissue-specific immune tolerance. We explore novel biology and therapeutic targets, with key interests spanning nucleic acid-based medicines, vaccines, and the intricate biology of innate immune cells and lymphocytes. This work aims to precisely restore immune balance, offering transformative potential for patients with autoimmune conditions.

Tr1 T cells are a class of immune-suppressive, self-regulating T cells that induce immune tolerance locally.  Parvus Therapeutics has developed a precision medicine platform termed navacims that couples disease-relevant peptide-MHCII complexes to iron-oxide nanoparticles shown to induce the differentiation of Tr1 T cells in vivo. This platform extends to inflammatory bowel disease, type-1 diabetes, multiple sclerosis, and other autoimmune conditions, showcasing the broad therapeutic potential of pMHC.

Extracellular vesicles (EVs) were engineered to carry immunomodulatory molecules like CD80, OX40L, and PD-L1. These engineered EVs successfully modulated human and murine T cell functions, altering disease progression in cancer and autoimmune hepatitis. Specifically, OX40L EVs enhanced antitumor activity with anti-CTLA-4 in melanoma. EVs with multiple immunomodulatory proteins (EVmIM) also engaged T cells and antigen-presenting cells, demonstrating their potential to elicit antitumor responses and modulate immune functions in various diseases.

Although B cell depleting therapeutic constructs have shown benefit in certain autoimmune diseases, attempts to effect broad T cell depletion have not been effective due to adverse effects of T cell aplasia. Due to the linkage between germline-encoded TCR variants and HLA alleles, close associations exist in HLA-associated autoimmune diseases. Using selective TCRVBeta BsAb's constructs we have demonstrated targeted depletion of autoreactive T cell subsets in human and murine models.

PD-1 is an inhibitory co-receptor expressed on autoreactive T cells. IDP-003 is a PD-1 agonist that pairs PD-1 in cis to CD2. CD2 ligand CD58 expression on APCs is required for activity, driving PD-1 phosphorylation, T cell suppression, and attenuation of xeno-GVHD. As CD58 is expressed on APCs and non-immune cells, IDP-003 should resolve pathology driven by autoantigens presented on both immune cells and non-immune cells in diverse autoimmune conditions.

In celiac disease, HLA-DQ2.5/gluten peptide complexes activate pathogenic CD4+ T cells. DONQ52 is a novel multispecific antibody designed to broadly engage diverse gluten peptide-loaded HLA-DQ2.5 molecules. This cross-reactivity aims to neutralize the immune cascade initiated by gluten. We detail DONQ52's antibody engineering, from lead identification to optimization, highlighting its broad binding characteristics and therapeutic potential for celiac disease.

Autoimmune diseases are entering a new era, fueled by both adapted immune-oncology technologies and therapies uniquely designed for autoimmune biology. This Think Tank will examine emerging modalities—mRNA, lipid nanoparticles (LNPs), gene editing, and cell therapies—identifying where IO approaches translate, where they need adaptation, and where distinct strategies are essential, while exploring how immune tolerance, safety, and cross-pollination between IO and autoimmunity can accelerate therapeutic innovation.

• What challenges do we face?
• What improvements do you apply?
• What might address future needs?

Think Tank 1: Emerging Modalities – The Role of mRNA, LNPs, Gene Editing, and Cell Therapies in Treating or Influencing Autoimmunity

Facilitators: 

Xin Luo, PhD, Scientific Researcher, MD Anderson Cancer Center​

Marco Ruella, MD, Assistant Professor, Scientific Director, Hematology and Oncology and Center for Cellular Immunotherapies, University of Pennsylvania

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Think Tank 2: How Do We Decide a Mechanism/Candidate Is Worth Exploring Further?

Facilitators:

William Bracamonte, MD, PhD, Clinical Professor, Rheumatology, University of Wisconsin

Marc A. Gavin, PhD, Senior Research Fellow & Head, Immunology, InduPro

4:35 pm Think Tank Report Out: Listen and Learn

During the Think Tank discussion, we shared experiences and working solutions for autoimmune diseases. Now, as a collective community, let’s hear from the facilitator as they share key discussion points and strategies, and provide a wrap-up of the conversation. What can we take away and apply in both autoimmune and IO settings?