Tumors are not simply collections of cancer cells; they are complex structures composed of blood vessels, immune cells, and supporting structures that interact, consume oxygen and other nutrients, and produce waste. Changing a tumor’s environment can have profound impacts on the efficacy of antitumor therapy. I will discuss the influence of microenvironmental modulators on immunobiology and our group’s approach to harness these interactions to improve therapeutic outcomes.

T cells have become the central focus of new cancer therapeutics. We recently performed in vivo CRISPR screens in CD8 cytotoxic T cells in tumor models of immunotherapy, which rediscovered prime immunotherapy targets, such as PD-1, TIM-3, LAG3, and previously undocumented targets. Other novel immunotherapy modalities will also be discussed.

Evaluation of a new chemical/biological entities (NCE/NBE) in tumor targeting therapies takes 5-12 years for development while only a few candidates reach clinics. One bottleneck is the absence of a reliable human model with an intact tumor micro-environment & data consistency. AXTEX-4D™ seals this gap and offer a suitable alternative. Drug-Tissueoid interactions, T cell migration, and validation of the tumor characteristics like necrosis, angiogenesis, EMT etc., broaden its scope in the modern discovery landscape.

Although T cells can be isolated directly from tumor-infiltrating lymphocyte (TIL) specimens, recent work has called into question whether or not these T cells are necessarily tumor-reactive or perhaps specific for viral or other antigens. We've looked across tumor indications at a number of patients to identify whether or not T cell receptor clonality and TIL gene expression analysis can be used to identify tumor-reactive T cells. Using a yeast-display system, the antigen specificities of these T cell populations can be identified and linked to the tumor.

In order to support the generation and efficacy of an antitumor response, we have designed trifunctional antibody-fusion proteins for tumor-directed combined delivery of IL-15 and costimulatory members of the TNF-superfamily, demonstrating enhanced immune responsiveness in vitro and antitumor activity in a mouse model in vivo.

HERA-GITRL is a member of a novel class of hexavalent TNFR superfamily agonists that share the natural ligand conformation. The biological activities of HERA-GITRL, boosting antigen-specific T cell response and anti-tumor efficacy in mouse models, are crosslinking independent. As the Fc-mediated mixed mode of actions observed for antibodies are avoided, HERA-GITRL is an excellent candidate for further development into a next-generation GITR agonistic immuno-oncology drug.

Development of effective CAR T cells targeting widely pan-T cell antigens for T cell leukemia and lymphoma has been hindered by frequent self-targeting of CAR T cells and possible induction of prolonged T cell aplasia. We developed fratricide-resistant, CD5 CAR T cells that produce high anti-tumor activity in patients with refractory or relapsed T cell malignancies, without eliminating healthy endogenous T cells.

Despite the unprecedented activity of CAR T cell therapy, the wider application is limited by the development of life-threatening toxicities of cytokine release syndrome and neurotoxicity. Here we will review new insights into the mechanisms of these toxicities and novel strategies to enhance CAR T cell safety.

Antibody drug discovery is as arduous and strenuous as finding a needle in a haystack. Single B cell technology (SBCT) is indispensable for accessing a large antibody repertoire of an immune-experienced animal and the ability to interrogate each individual cells, rather than to measure the average of a cell pool. In this talk, we will: 1) introduce the general approaches of SBCT; 2) GenScript offerings with case study; 3) summarize the advantages of SBCT screening.

This presentation will discuss the technical considerations when developing cord blood NKs, alongside frequent obstacles, gene modification protocols, and potential applications.

In this talk, we will discuss combining multiple methods, including immunization strategy, single plasma B cell cloning on the Beacon platform and the use of transgenic animals to significantly reduce the cycle times while rapidly identifying high affinity functional antibodies.

Vγ9Vδ2 T cell activation leads to broad functional activities against tumors. Tumor-infiltrating γδ T cells are the most significant favorable cancer-wide prognostic signature. Anti-tumoral response of Vγ9Vδ2 T cells requires sensing of phosphoantigens accumulated through binding of butyrophilin 3A(BTN3A) expressed in tumors. We identified butyrophilin 2A (BTN2A) as a requirement for BTN3A-mediated, Vγ9Vδ2 T cell cytotoxicity against cancer cells.

ImCheck Therapeutics is developing a first-in-class activating, humanized antibody to butyrophilin 3A (BTN3A) for the treatment of cancer. ICT01 binds to BTN3A, and specifically primes a broad range of tumor cells for killing by gamma-delta (Vg9-Vd2) T cells. ICT01 has entered early-stage clinical trials in solid tumors and hematological malignancies. Therapeutic antibodies targeting several novel butyrophilins are also currently at various stages of preclinical development. This opens a new space, clearly differentiated from the current B7/CD28 family of targets, potentially ushering in an unexplored novel avenue for next-generation cancer immunotherapy.

The Membrane Proteome Array (MPA) platform de-risks lead selection by testing biotherapeutics for specificity and off-target binding. This platform contains over 6,000 human membrane proteins, each expressed in live cells in their native conformation. In the process of testing hundreds of antibodies, we found up to 20% of antibodies exhibit off-target binding. We used our high-resolution Shotgun Mutagenesis epitope mapping platform to understand these observations and explain how some mAbs can bind completely unrelated proteins.

Sangamo Therapeutics is a clinical-stage genomic medicine company focused on gene therapy, cell therapy, and in vivo genome editing and gene regulation. This presentation will highlight preclinical data for several technology platforms and therapeutic programs.

Pathologies produced by activated alloimmune T cells are a major cause of morbidity and mortality in patients following allogeneic bone marrow or solid organ transplant. We have developed engineered T cells that selectively recognize and eliminate pathogenic lymphocytes, and prevent disease progression without producing systemic T cell elimination.