ABIO-0501

TALL-104 and NK-92MI-mediated cell killing assays were used to examine the immune resistance of UM cells...Notably, lactate secreted by IL-6-treated UM cells was crucial in influencing PD-L1 and HLA-E stability via the GPR81-cAMP-PKA signaling pathway. Our data reveal a novel mechanism by which UM cells acquire an immune-escape phenotype by metabolic reprogramming and reinforce the importance of the link between inflammation and immune escape.

Knockdown of VE-cad or the PD-L1 gene ablated the effects of YKL-40 and reinvigorated TALL-104 cell immunity against vessels. In summary, our study demonstrates a novel vascular immune escape mechanism by which mGBM promotes tumor vascularization and malignant transformation.

Fluorescently labeled wild-type HCT-116 colorectal cancer cells and TALL-104 T-cells were co-cultured and treated with GLPG-0187, a small molecule integrin inhibitor, at various doses. Probing for additional downstream markers of TGF-β and up-stream markers of PD-L1 will help to further elucidate this mechanism. Further co-culture experiments will also include anti-PD-L1 and anti-PD-1 therapy to investigate the viability of integrin inhibition as an adjuvant to immune checkpoint blockade.

GLPG-0187 promoted significant immune cell killing of the CRC cells by TALL-104 T lymphoblast cells and reduced phosphoSMAD2 in HCT116 p53-null cells either in the absence or presence of exogenous TGF-β. Our results suggest that TGF-β signaling inhibition by a general integrin receptor inhibitor may boost T-cell killing of MMR-deficient colorectal cancer cells and suggest that a combination of anti-GDF-15 in combination with TGF-β blockade be further investigated in the treatment of MMR-deficient mCRC. Our results support the development of a novel immune-based therapeutic strategy to treat colorectal cancer by targeting the TGF-β signaling pathway through integrin receptor blockade.

Phase 1 clinical trials are ongoing for treatment of primary liver cancer and uveal melanoma with liver metastases using pressure-enabled drug delivery of SD-101 in combination with systemic immune checkpoint inhibitors (ICIs). Combination PMD and ICI studies are needed to inform drug combinations and dosages in syngeneic murine models of primary liver cancer and CRCLM. Subcutaneous and orthotopic tumor models are expected to demonstrate the efficacy of local PMD treatment with systemic immunotherapy.

CRC and GBM cells were co-cultured with TALL-104 cells -/+ TMZ and -/+ ICI to measure TALL-104-mediated cell death. Our results indicate that TMZ sensitizes MSS, MGMT-expressing CRC cells to ipilimumab + nivolumab ICI. Importantly, this suggests that TMZ-mediated sensitization to ipilimumab + nivolumab is independent of MGMT status and the patient cohort that may benefit TMZ + ipilimumab + nivolumab may be expanded to CRC patients with MGMT-expressing, MSS tumors.

The standard treatment options are surgery, radiation therapy, and chemotherapy using temozolomide. Immune cell co-culture, comprising of GBM cell lines plus TALL104 human leukemia T cells, was used to determine the amount of tumor cell death with palbociclib, pembrolizumab and a combination at different time points in both normoxia and hypoxia conditions. Our results are providing insights into improving immune checkpoint therapy for GBM patients.

Additionally, both cancer cell lines as well as TALL-104 T-cells and NK-92 NK cells were treated with 0.5 μM 9-ING-41 for 24 hours and harvested for Luminex cytokine profiling. The treatment cohorts for these experiments include 9-ING-41 combined with either anti-PD-L1, anti-PD-1, or anti-CTLA-4 immune checkpoint inhibitors. Our results suggest a promising combination therapeutic strategy for patients with soft tissue and bone sarcomas and future work will strive to better elucidate the mechanisms of efficacy.

However, GLPG-0187 promoted significant immune cell killing of the CRC cells by TALL-104 T lymphoblast cells. Our results suggest that TGF- signaling inhibition by a general integrin receptor inhibitor may boost T-cell killing of MMR-deficient colorectal cancer cells, and suggest that a combination of anti-GDF-15 in combination with TGF- β blockade should be further investigated in the treatment of MMR-deficient mCRC. Our results support the development of a novel immune-based therapeutic strategy to treat colorectal cancer by targeting the TGF-β signaling pathway through integrin receptor blockade.

Applying this BsAb in a T cell-Tumor cell co-culture system showed that targeting both PD1 and AGR2 with this BsAb induces the attachment of TALL-104 (CD8 T-lymphocytes) cells onto co-cultured H460 AGR2 Lung tumor cells and significantly reduces migration of H460 cells...These effects are significantly reduced with AGR2 expression negative WI38 cells. Our results demonstrate that the AGR2xPD1 BsAb could be a potential therapeutic agent to provide better solid tumor targeting and synergetic efficacy for treating AGR2+ cancer by blocking AGR2 paracrine signaling to reduce tumor survival, and redirecting cytotoxic T-cells into AGR2+ cancer cells.

Jurkat T lymphocytes, TALL-104 cytotoxic T cells and primary human and mouse CD3-positive T lymphocytes were employed for immune evasion studies...As such, personalised targeted immunotherapy could be adapted. Further investigations required to map the immune evasion machinery for each type of cancer and design the best targets for personalised immunotherapy of human malignancies.