Therapeutic progress has thus far been limited with cellular therapies in advanced solid tumors, due to limited observed efficacy and treatment-related toxicities. Advanced prostate cancer represents a compelling model for CAR T therapy. We will review current mechanisms and rationale for re-directed T cell therapies for advanced prostate cancer; describe an early experience with CAR T therapy for advanced prostate cancer; and discuss challenges and future approaches for prostate cancer CAR T therapy.

Prostate cancer is first solid tumor with an approved autologous immunotherapy with a survival benefit. This treatment has had limited impact on the biomarker, Prostate Specific Antigen (PSA) with minimal antitumor effects. Prostate cancer remains suboptimally responsive to other immunologic approaches including checkpoint inhibitors, or vaccines but with some activity seen using bispecific T cell engagers (BiTEs) and Chimeric Antigen Receptor (CAR) T cells. Strategies to improve the conversion of what is deemed as an immunologically “bland” microenvironment to one that is immunologically “hot” is the focus for PSMA-directed CARs in patients with metastatic castration resistant prostate cancer (mCRPC).

T cell activation is initiated upon binding of the T Cell Receptor (TCR)/CD3 complex to peptide-MHC complexes (“signal 1”); activation is then enhanced by engagement of a second “co-stimulatory” receptor, such as CD28 on T cells binding to its cognate ligand(s) on the target cell (“signal 2”). However, tumors evade the immune system often by downregulating one or both of these signals 1 and 2. We developed a class of bispecific antibodies that mimic signal 2, by bridging a second tumor associated antigen (TAA) to CD28 on T cells. Combining this novel class of co-stimulatory bispecific antibodies with PD-1 mAb or the emerging class of TAAxCD3 bispecifics may provide well-tolerated, “off-the-shelf” antibody therapies with potentially enhanced anti-tumor efficacy.

The development of next-generation bispecific gamma-delta T cell engagers (bsTCE) with a widened therapeutic window characterized by high potency and high tumor selectivity has strong potential. Lava Therapeutics’ platform is based on the selective recruitment of  Vγ9Vδ2 T cells for eradicating tumor cells. This presentation will discuss our bsTCEs designed to engage Vγ9Vδ2 T cells against tumor cells expressing PSMA for the development of novel therapeutics in prostate cancer.

Autologous T cell therapies have been life-changing for many patients; but virus-specific, allogeneic platforms hold the promise of effective, off-the-shelf treatments manufactured at scale, and delivered to patients within days. In this talk, the flexibility and advantages of EBV T cells and how allogeneic treatments may change the treatment paradigm for cancer and autoimmune diseases will be discussed.

Activating NK cell receptors represent promising target structures to elicit potent anti-tumor immune responses. We have generated efficient NK cell engagers that bridge Natural Cytotoxicity Receptor NKp30 on NK cells with EGFR on tumor cells in several multifunctional IgG-like bispecific formats. In this talk I will discuss different strategies for targeting NKp30.

Transmembrane proteins (TPs) are embedded in the cell membrane and span the intracellular and extracellular environments. The transmembrane region directly interacts with the phospholipid bilayer and is an important channel bridging these environments enabling transport of various ions and molecules and relaying activation and response reactions to extracellular stimuli. These reactions propagate intracellularly through downstream signaling pathways and regulate cell metabolism, cellular activity, and cellular fate. TPs have broad applications in cancer immunotherapy and autoimmune diseases. Our team has engineered methods to formulate TPs to support research in understanding the role of various diseases.

Adoptive cell therapies have demonstrated remarkable outcomes in hematologic malignancies, but efficacy in solid tumors is still lacking. We have established a novel, proprietary monocyte and macrophage based cell therapy platform based on chimeric antigen receptor macrophages (CAR-M). In this talk we will review the CAR-M platform, present novel preclinical data, and discuss the ongoing Phase I, first-in-human CAR-M trial for HER2+ metastatic solid tumors.

Advancements in cellular engineering have led to the development of novel strategies aimed at overcoming current challenges. In this presentation, we will discuss the advantages of allogeneic NK cells as a resource for cell therapy. We will focus on strategies to leverage the intrinsic anti-tumor properties of NK cells, and will discuss our work to develop novel approaches to enhance NK function and persistence though genetic engineering.

Tumor-selective antigens to direct CAR binding are scarce for treating solid malignancies. However, tumor selectivity is crucial as on-target off-tumor activation of CAR T cells can result in potentially lethal toxicities. We have engineered a stringent oxygen-sensing system ‘HypoxiCAR’ which restricts CAR expression to hypoxic microenvironments, such as is found in solid tumors. In preclinical models, HypoxiCAR T cells provide robust anti-tumor efficacy while avoiding systemic toxicities associated with on-target off-tumor activation.

GammaDelta Therapeutics is developing allogeneic cell therapy platforms based on Vd1 (γδ) T cells. We are exploiting the biology and characteristics of these unconventional T cells to progress differentiated products for adoptive cell therapy of hematologic malignancies and solid tumors.

T cell-derived induced pluripotent stem cells (TiPSCs) provide a powerful platform for unlimited production of specific T cells. Initial differentiation platforms facilitated development of innate-like T lymphocytes. Through careful adjustment of the Notch and ITAM signaling, we can facilitate alpha-beta T lineage commitment, while utilizing the CAR to drive the cells through T cell development and maturation.

Banked, allogeneic therapeutic T-cells overcome problems related to manufacturing failures of patient derived products, the length of time for manufacture and testing of products, product potency and expense, and are the holy grail for cellular Immunotherapy. Major problems that beset allogeneic T-cells are graft versus host disease and graft rejection mediated by donor- and host-derived alloreactive T-cells respectively. We are using banked EBV-specific T-cells (EBVSTs) modified to express a CD30.CAR for the treatment of allogeneic patients with CD30-positive lymphoma with impressive clinical responses. The use of EBVSTs solves the problem of GVHD, since with their more limited TCR repertoire, EBVSTs have not cause GVHD in hundreds of allogeneic recipients, while host alloreactive T-cells upregulate CD30 on stimulation, so that they can be eliminated by the CD30.CAR, thus preventing rejection.