HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into basic, translational and clinical cancer research from MD Anderson experts. This special edition features presentations by MD Anderson researchers at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting on radiation-induced immune activation in colorectal cancer, response biomarkers in soft tissue sarcoma, STING-mediated immune remodeling in pancreatic cancer, improved TIL manufacturing and engineering approaches, and early immunotherapy clinical trial results.
Colorectal cancer cells suppress radiation-induced immune priming by elevating CD47 and PD-L1 (Abstract 592)
Radiation therapy can prime anti-tumor immune responses in patients with colorectal cancer, but unirradiated tumors can escape immune surveillance. A research team led by Rodney Cheng-En Hsieh, M.D., and Michael Curran, Ph.D., discovered how these tumors avoid immune recognition and identified a potential treatment approach to improve responses. Hsieh will present the findings in the SITC Presidential Session on Nov. 13.
In response to radiation, colorectal cancer cells activated the ATR signaling pathway, increasing levels of “don’t eat me” signals CD47 and PD-L1. Similarly, patients with rectal cancers who respond poorly to neoadjuvant radiation therapy had significantly higher levels of CD47 after treatment. These signals engage with their corresponding receptors, SIRPα and PD-1, on antigen-presenting cells (APCs) to block phagocytosis, or ingestion, of cancer cells by APCs – which ultimately suppresses immune activation.
In preclinical models, blocking SIRPα and PD-1 during radiation therapy profoundly enhanced immune priming and increased production of anti-tumor T cells. This combination improved responses in both irradiated and unirradiated tumors and prolonged survival in multiple models.
Infiltrating immune cells offer potential biomarker for soft tissue sarcomas treated with neoadjuvant immunotherapy (Abstract 379)
Immune checkpoint inhibitors have shown activity for patients with metastatic soft tissue sarcomas, including undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). To evaluate the benefits in the neoadjuvant setting, Christina Roland, M.D., and Neeta Somaiah, M.D., led a Phase II study for patients with localized UPS or DDLPS. On Nov. 12, Emily Keung, M.D., will present findings on biomarkers of patient responses, which have important implications for researchers working to optimize treatments.
The trial included 17 patients with DDLPS and 10 with UPS, randomized to receive either nivolumab or nivolumab and ipilimumab, with UPS patients receiving concurrent radiation therapy. Pathologic response, assessed at the time of surgery, was observed in three patients (18%) with DDLPS and nine (90%) with UPS. At a median follow up of 23 months, 44% of all patients had experienced a relapse and 14% had died due to recurrence.
The presence of tumor-infiltrating B cells and cytotoxic T cells at the beginning of treatment was associated with better survival outcomes in both patient groups. Conversely, the presence of T-regulatory cells was associated with poorer responses and resistance to checkpoint blockade.
Study uncovers mechanisms behind STING-mediated immune remodeling in pancreatic cancer (Abstract 758)
Pancreatic cancers have immune-suppressive tumor microenvironments (TMEs) and do not typically respond well to immune checkpoint inhibitors. STING pathway activation can remodel the TME, increase T cell infiltration and improve anti-tumor immune responses, but it is unclear how this occurs. Researchers led by Casey Ager, Akash Boda and Michael Curran, Ph.D., discovered that STING activation repolarizes suppressive myeloid cells and identified a strategy to overcome resistance to checkpoint blockade. Boda will present the findings on Nov. 13.
The researchers profiled myeloid-derived suppressor cells and M2 macrophages following activation of the STING pathway using cyclic dinucleotide (CDN) agonists. They demonstrated that STING agonists work in part by inhibiting c-Myc signaling and altering cellular metabolism to drive a proinflammatory conversion.
Injection of the STING agonist, IACS-8803, developed in collaboration with MD Anderson’s Therapeutics Discovery division, amplified responses to immune checkpoint inhibitors in preclinical models of pancreatic cancer. These results suggest STING agonists may be used to overcome resistance to checkpoint blockade in this aggressive cancer.
New methods for expanding and engineering TIL therapies may improve manufacturing speed and potency
Tumor-infiltrating lymphocyte (TIL) therapy, which utilizes immune cells isolated directly from a patient’s tumor, has shown promise in clinical studies for a variety of tumor types. However, in some cases, the TILs require engineering to overcome immune checkpoints or suppressive immune signals. Building upon longstanding expertise, MD Anderson researchers will share new approaches for TIL expansion and engineering that offer paths to speed production and improve anti-tumor activity.
- Clinically-scalable approach for generating ovarian cancer TILs resistant to suppressive TGFβ signaling using CRISPR/Cas-9 gene editing, presented by Samantha Fix, Ph.D. (Abstract 172)
- Improved method for culturing lung cancer TILs with interleukin 2 (IL-2) in combination with CD3 and 4-1BB agonists to speed manufacturing and enrich CD8+ T cells, presented by Meredith Frank (Abstract 174)
Trials in progress offer early look at new immunotherapy approaches
MD Anderson researchers will present a variety of clinical trials in progress, designed to evaluate the safety and anti-tumor activity of novel immunotherapy approaches, with encouraging early results. Highlights include:
- Phase II trial of NT-17, a long-acting form of interleukin-7, plus pembrolizumab in patients with advanced pancreatic cancer, presented by Aung Naing, M.D. (Abstract 408)
- Phase I trial of Nous-209, an off-the-shelf neoantigen vaccine, combined with pembrolizumab for patients with tumors harboring mismatch repair deficiencies or high microsatellite instability, presented by Michael Overman, M.D. (Abstract 410)
- Phase I trial of GEN-009, a personalized neoantigen vaccine, combined with a PD-1 inhibitor in patients with advanced solid tumors, presented by Maura Gillison, M.D., Ph.D. (Abstract 485)
- Phase I trial of SRK-181, an inhibitor of latent TGFβ1, alone in combination with anti-PD-(L)1 therapy in patients with advanced solid tumors, presented by Timothy Yap, M.B.B.S., Ph.D. (Abstract 532)
- Phase Ib/II trial of NKTR-255, an interleukin-15 agonist designed to boost natural killer (NK) cell activity, in combination with cetuximab in patients with advanced solid tumors, presented by Mehmet Altan, M.D. (Abstract 957)
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