Adenosine is a powerful T cell immunosuppressant, measurable at micromolar concentrations in a range of solid tumors. We have decoded an important but underappreciated mechanism whereby adenosine, taken up by T cells via the Equilabrative Nucleoside Transporter 1 (ENT1), poisons pyrimidine synthesis. EOS-984 is a clinical-stage ENT1 inhibitor with the potential to shield T cell-activating agents from this mechanism, unlocking their full potential in solid tumors.

TCR-T cell therapy is a promising approach with high specificity and sensitivity to low-abundance antigens, targeting both surface and intracellular proteins. In contrast, mAbs and CAR T cells only target surface antigens. However, challenges in manufacturing, cost, and accessibility exist. To address these, TCR-based bispecific T cell engagers (BiTEs) offer a potential solution. This presentation will outline the challenges and development pathway for TCR-based BiTEs in cancer treatment.

Haploidentical NK cells can induce remissions in patients with refractory leukemia. However, they lack specificity. To make NK cells antigen-specific, we developed Trispecific Killer Engagers (TriKEs) that engage NK cells (camelid anti-CD16) and tumor-antigens with IL-15 between them. The goal of this therapy is to create immune synapses in vivo to target and activate endogenous NK cells to optimally treat leukemia (anti-CD33) and solid tumors (B7H3).

Targeted therapy with covalent inhibitors of oncoproteins are initially effective but lack durability due to cancer cell resistance. MHC-I presentation of the covalently modified oncoprotein peptides on the cell surface creates synthetic neoantigens that can be targeted by antibodies with high specificity and affinity. As T cell engagers, these HapImmune antibodies afford a unique combination of targeted and immune therapy. Preclinical proof-of-concept studies based on oncoprotein KRASG12C will be presented.

Tumor-specific CD4 T cells correlate with better clinical outcomes and activation of myeloid and CD8 T cells across human cancers. Mouse models show that CD4 T cell therapy can control tumors through stimulation of CD8 T cells, and through CD8 T cell independent innate immune mechanisms. I will discuss methods to target CD4 T cells to solid tumors, and methods to understand and augment antitumor mechanisms.

Tumor-target heterogeneity presents a major obstacle for immunotherapies, often resulting in incomplete tumor elimination and treatment resistance. This talk will present our work advancing a novel class of T cell-redirecting multispecific antibodies that addresses this problem. Our single-molecule approach converts target-negative cells into target-positive cells by transforming endogenous tumor self-defense mechanisms into targetable vulnerabilities.

IOMX-0675 is a fully human, cross-specific antibody identified from iOmx's proprietary phage display library, selectively antagonizing with high affinity the two immunosuppressive receptors LILRB1 and LILRB2, while binding only weakly to the closely related immune-activating family members LILRA1 and LILRA3. Its highly differentiated binding profile drives potent reprogramming of the immunosuppressive myeloid compartment and restoration of cytotoxic lymphoid cell activity in the tumor microenvironment. Highly promising preclinical data strongly support a best-in-class approach for IOMX-0675 in an evolving novel target space for cancer immunotherapy.

In 2021, seminal experiments demonstrated that autologous CD19-CAR-T cells, targeting antibody-producing B-cells, could be generated and used to treat patients with severe lupus. Over the past four years, it has become apparent that several CAR-T and T-cell engaging (TCE) bispecific antibody approaches, using constructs previously relegated primarily for treatment of cancer, may be used to deplete B cells producing pathogenic autoantibodies in autoimmune diseases. While these therapeutic approaches can come with potential adverse effects such as cytokine release syndrome (CRS) and sometimes neurological sequelae, they are offering hope as new treatment approaches for a wide variety of severe autoantibody-directed autoimmune diseases. The various CAR-T and TCE bispecific antibody approaches being developed today for autoimmune diseases will be described and compared.

TL1A-blocking antibodies have demonstrated promising clinical remission rates for patients with inflammatory bowel disease. TL1A promotes inflammation through binding to a single receptor, DR3. Preclinical studies demonstrated a dominant role for DR3 in suppressing inflammation relative to TL1A. The preclinical development, safety, PK, and PD of a DR3 blocking antibody, SL-325, now entering Phase 1 clinical development, will be presented.

LAG-3 correlates with aPD-1 resistance but LAG-3hi tumor-bearing mice, resistant to aPD-1, responded to aPD-1+aLAG-3 therapy. The efficacy of combination aPD-1+aLAG-3 immunotherapy in mice and a cohort of patients with metastatic melanoma was associated with Treg destabilization. These data indicate that combination aPD-1+aLAG-3 immunotherapy drives Treg phenotypic plasticity, which represents a novel biomarker of response and a putative therapeutic target to improve outcomes.

We develop trifunctional antibody-fusion proteins composed of a tumor-directed antibody moiety and two different immunomodulatory molecules-common gamma chain receptor cytokines & costimulatory ligands of the TNF-superfamily. Aiming for improved localization and efficacy at the tumor site, the design focuses on targeted presentation and combined mode of action.

We have successfully engineered non-pathogenic gut bacteria to surface-display various cytokines, including IL15, IL18, and IL21. The bacteria displaying decoy-resistant IL-18 demonstrated safety and potent efficacy in murine colorectal cancer and melanoma mouse models alone and synergistically with checkpoint blockade, curing a significant proportion of mice. Further, treatment with the bacteria also boosted the migration and efficacy of human CAR NK cells in NSG mice bearing mesothelioma.