Breast cancer (BC) is the second leading cause of death for worldwide. BC is classified as one disease; it’s challenging to treat due to numerous subtypes and varying treatment regimens. Surgical and systematic advancements have modified the standard care for BC to include immunotherapy among other treatments. BC immunotherapy has expanded to (1) antibody-based treatment, (2) cytokine treatment, (3) immune checkpoint inhibitors, (4) adoptive T-cell therapy, and (5) anti-cancer vaccines.

Natural killer cells showed great promise for treating cancers. However, challenges such as the short persistence of NK cells and suppressive tumor microenvironment limit its clinical benefits. While donor-derived NK products consist of a mixed population, the iPSC-derived NK cells are homogenous. Here, the efficiency and off-target effects of candidate TALENs® in iPSCs were analyzed before use. The IL15^+/+/TGFbR2^-/- dual-edited iPSCs kept their pluripotency, exhibited normal morphology and karyotype, and were able to differentiate and expand into NK cells with high efficiency. These dual-edited iNK cells showed enhanced persistence without exogenous cytokines and are resistant to suppressive TGFß signaling.

Previous research indicates the necessity of attenuating PD-L1 and TGFß signaling to trigger efficacious anti-tumor responses. Our study reveals that TGFß and PD-L1 restrict expansion of stem cell–like CD8 T cells (TSCL), blocking both expanded TSCL and enhanced motility and accumulation of IFNghi cells—transforming the tumor ecosystem to be broadly immune-supportive—and underlying the role of TGFß and PD-L1 in maintaining intratumoral CD8 T cells in a dysfunctional state.

OBX-115 engineered TIL cell therapy utilizes cytoDRiVE® platform to enable regulation of functional membrane-bound IL15 by reversibly modulating protein stability, enabling a lower dose of lymphodepletion than conventional TIL therapy, obviating the need for IL2, and allowing regulation of antigen-reactive TIL expansion. In a first-in-human study, OBX-115 has produced promising response rates in patients with immune checkpoint inhibitor-refractory advanced melanoma, without any dose-limiting toxicities or Gr 4 treatment-emergent non-hematologic toxicity.

Tumor-reactive CD8+ T cells are predominantly found in the tumor microenvironment with an exhausted phenotype. We sort CD8+ TIL that coexpress CD39 and CD103, and expand these cells from thousands to billions to generate adoptive T cell products that are highly enriched for cells that can recognize and kill autologous tumors. We have tested the utility of this approach with coculture assays, PDX models and in patients with metastatic cancer.

• Currently available non-engineered TIL cell therapy requires use of high-dose IL2, which has well-described high-grade toxicity that limits patient eligibility

• Novel approaches are needed to improve the safety of TIL cell therapy to enable a broader patient population to benefit

• Discussion will focus around existing approaches to improve safety as well as potential avenues to explore in future trials​

• Challenges with NK cell therapy development
• Pros and cons of NK approaches compared to other cell-based therapeutics
• Applications of NK therapies to solid tumor indications
• Future directions of NK therapies

In this presentation we discuss a molecule (TriKE) to link natural killer (NK) cells to cancer cells expressing B7-H3. This molecule activates and expands NK cells, killing B7-H3 positive cancer cells in lab tests and shrinking tumors in mice.

This research explores modifying a patient's tumor-infiltrating lymphocytes (TILs) to enhance their ability to fight solid tumors. This approach holds promise for a more targeted and effective immunotherapy, potentially offering a new weapon against a wide range of cancers.

Preliminary data suggest that mast cells are enriched in BRAF mutant colorectal cancer. However, the role of mast cells in the progression of this aggressive subtype of colorectal cancer is not known yet. My preliminary results suggest that mast cells are recruited by factors secreted by colon cancer secretory cells. In turn, mast cells promote epithelial-to-mesenchymal transition in BRAF mutant colorectal cancer cells in a contact-dependent fashion.

Human pluripotent stem cells (PSCs) offer unlimited cell source for cell therapies. Major challenges are (1) complexity of bioprocessing, and (2) outdated regulatory guidelines. HebeCell’s proprietary protoNK platform is a first-in-class technology enabling large-scale PSC-derived NK cell production. To translate protoNK platform into clinic, we have (1) successfully established internal manufacturing capability, and (2) we are working towards the 1st IND using protoNK to treat pulmonary metastasis of Ewing sarcoma.

This presentation explores strategies to surmount the immune barrier in allogeneic cell therapy. Addressing challenges of host immune rejection and graft-versus-host disease, it highlights approaches such as immune modulation and genetic engineering to enhance tolerance and efficacy. By overcoming these hurdles, allogeneic cell therapies hold the promise of broader applicability and improved outcomes, propelling the field towards transformative advancements in regenerative medicine.

This research explores high-efficiency methods for large-scale production of CAR NK cells. CAR NK cells are a promising immunotherapy approach, but large-scale manufacturing is a hurdle. This study examines strategies to overcome this bottleneck, paving the way for wider use of CAR NK cell therapies.

This talk explores how translational science informs the development of cell therapies. It will examine how researchers bridge the gap between basic research and clinical trials, using Adaptimmune as a case study. This approach helps ensure new cell-based treatments are effectively tested and developed.