Cellular therapy, particularly with CAR T cell technology, has dramatically improved outcomes for many patients with hematologic malignancies, but treatment of solid tumors has been more challenging. Advances in adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) are now bringing the promise of cellular therapy to solid tumor histologies. This presentation will highlight advances in TIL technology, data on clinical efficacy, and areas for future development.

Engineered T cell receptor-based targeting NYESO-1 and MAGEA-4 have shown promise as treatment options for some patients with soft tissue sarcomas such as synovial sarcoma and myxoid round cell liposarcoma. There are ongoing efforts to understand the mechanisms of response and resistance in these patients, expanding applicability of this technology and optimizing and improving duration of response.

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown durable responses in patients with metastatic melanoma and other epithelial malignancies. In preclinical studies, next generation TIL therapy approaches have shown the potential to increase response rates and duration of response in difficult to treat solid tumors. We have developed a genetically modified TIL product, IOV-4001, using TALEN® technology licensed from Cellectis to inactivate the gene coding for PD-1. This genetic modification is expected to enhance the antitumor activity of TIL by counteracting the suppressive effects of the PD-1/PD-L1 signaling pathway directly on tumor reactive TIL. IOV-4001 is currently in a Phase 1/2, first-in-human study investigating the safety and efficacy of IOV-4001 in patients with previously treated metastatic non-small cell lung cancer (NSCLC) or advanced melanoma. This is a first of various next generation approaches at Iovance to optimize TIL phenotype, function, persistence, trafficking and tumor reactivity.

Tumor infiltrating lymphocytes (TILs) are phenotypically and functionally heterogeneous.  Only a fraction recognizes tumor antigens, and the rest are tumor non-reactive bystanders.  AgonOx recently showed that sorting CD8+ TIL based on co-expression of CD103 and CD39 highly enriched for tumor-reactive T cells from a variety of tumor types. We hypothesize that enriching for tumor-reactive T cells will significantly improve the clinical efficacy of autologous TIL adoptive cell therapy (ACT). Our strategy generates functionally active cytotoxic CD8+ T cells that can efficiently kill autologous tumor in vitro and in vivo in an ACT xenograft model using a patient-derived autologous tumor.

We have developed an integrated mechanism to interfere with PD1-mediated immune suppression by enhancing functions of TCR Ts that express a potent tumor-specific TCR with an integrated switch receptor, that uses the PD1 binding domain to interaction with PD-L1 but switches to activation of the T cells by 41BB signals inside the T cells. This serves as an integrated IO combination therapy that is dependent upon TCR activation and avoids system impacts of PD1/PD-L1 inhibitors using monoclonal antibody interventions.

• Advances in Gamma Deltas - antibody and cell-based approaches
  
• New approaches to cellular immunotherapy
  
• Overcoming the TME
• Combination approaches

There is increasing interest in gamma T cell therapies as a multifunctional approach to solid tumors due to deficiencies in otherwise successful therapies for hematologic malignancies. We will review anti-cancer aspects of gamma T cell biology, optimal conditions for effective anti-tumor efficacy gamma T cells, approaches that are currently being tested in patients, and standard-of-care combinations with gamma T cells that can create synergies with the potential for long-term success.

Gamma delta T cells are an attractive platform for off-the-shelf, allogeneic CAR T-cell therapy. ADI-001, the first CAR-engineered gamma delta T cell product to reach the clinic, consists of allogeneic peripheral blood Vd1 gamma delta T cells expressing a second-generation CAR directed against CD20. We will discuss available clinical data from the ongoing Phase I trial of ADI-001 in patients with Non-Hodgkin’s Lymphoma.

Immune responses span interconnected regulatory modalities within and across cells. This talk will describe the latest developments in coupling CRISPR-based technologies, single-cell genomics, multiplexed imaging, and machine learning to uncover mechanisms controlling antigen-dependent and independent immune recognition and response. I will present recent findings, revealing intrinsic and extrinsic regulators of NK and T cell function and cellular/tissue immunogenicity, and describe massively parallel multiplexed systems for identifying immunomodulating interventions at scale.

Vg9Vd2 T cells are attractive effector cells for cancer immunotherapy due to their powerful cytolytic and pro-inflammatory properties and the positive correlation between tumor infiltration and good prognosis. ICT01, a novel anti-BTN3A mAb activating Vg9Vd2 T cells, is being evaluated in Phase I/IIa clinical studies (NCT04243499). ICT01 shows potent ability to modulate anti-tumor immune response by activating Vg9Vd2 T cells and broadening the immune response in the tumor microenvironment. Here, we will discuss the immune modulatory capacity of ICT01 and the next paths for combination approaches.

Natural killer (NK) lymphocytes interrogate cancer cells by recognizing ligands that are up or downregulated and attached antibodies that induce antibody-dependent cell-mediated cytotoxicity (ADCC). We have engineered induced pluripotent stem cell (iPSC)-derived NK (iNK) cells to express the high-affinity fusion FcyR CD64/16 to enhance their anti-tumor antibody binding and ADCC potency. iNK CD64/16A cells can be armed with tumor-targeting antibodies, cryopreserved, and thawed for immediate infusion. The coupled antibodies can be easily exchanged as a means of preventing tumor cell escape and targeting different malignancies.

The immunosuppressive tumor microenvironment (TME) of solid tumors is a barrier to cellular and immunotherapies. Myeloid cell-derived tumor associated macrophages (TAMs) accumulate in tumors but frequently are co-opted by tumors cells into supporting tumor growth. We developed the Activate, Target, Attack & Kill (ATAK) myeloid cell platform to engineer myeloid cells to recognize and phagocytize tumor cells as well as orchestrate a broad anti-tumor immune response against solid tumors.

Peptide-HLA (pHLA)-targeting therapeutics have shown clinical success in treating solid tumors. However, challenges related to safety exist: major concerns surrounding the ability of therapeutics to discriminate between on- vs off-target while maintaining high-potency. Therefore, approaches that discover optimal TCRs, and platforms to comprehensively identify potential off-targets, are critical to de-risking and accelerating therapeutic development. We have developed a strategy that (1) queries the TCR repertoire to enrich and identify active, sequence-distinct TCRs; (2) uses 3T-TRACE, a high-diversity pHLA library, to screen for cross-reactivity; and (3) exploits functional selections to simultaneously optimize for potency and specificity.

Triumvira develops autologous and allogeneic T cell therapies engineered with the T cell Antigen Coupler (TAC) receptor that redirects T cells to the respective antigen on tumor cells and activates T cells by co-opting the endogenous T cell receptor complex independently of MHC. Preclinical models have shown tumor clearance with minimal toxicity.

SUPLEXA therapeutic cells are comprised of activated autologous NK, NKT and T cells of both the gamma-delta and alpha-beta varieties, which are capable of recognizing and killing a broad range of tumor cells. They are manufactured in a robust and cost effective 2-week process beginning with patient-derived PBMC isolated from 50 mL of peripheral blood. The key step in the manufacturing process involves a coincubation of the PBMC with proprietary engineered tumor cells that express a variety of immunomodulatory ligands. A first-in-human clinical basket study is underway in Australia that includes patients with solid tumors and hematologic malignancies.