Researchers from The University of Texas MD Anderson Cancer Center presented promising results from three innovative clinical trials at the American Association for Cancer Research (AACR) Annual Meeting 2025. The studies showcase novel approaches to treating challenging cancers, including a personalized vaccine for colorectal cancer, targeted radiation therapy for kidney cancer, and engineered exosomes for pancreatic cancer.
Personalized Vaccine Shows Promise for Difficult-to-Treat Colorectal Cancer
Patients with microsatellite-stable metastatic colorectal cancer (MSS mCRC) typically face poor outcomes and limited treatment options after standard chemotherapy fails. This is largely due to the "cold" tumor microenvironment that limits immune system engagement.
A team led by Drs. Saurav Daniel Haldar and Michael Overman developed a personalized vaccine platform called NeoAg-VAX that utilizes advanced bioinformatics and sequencing tools. The platform delivers up to 10 tumor-derived proteins specifically targeted to each patient's unique mutation profile.
In their Phase I feasibility study, the researchers evaluated the personalized vaccine both alone and in combination with pembrolizumab immunotherapy in 28 patients with MSS mCRC. Results presented on April 27 demonstrated that the personalized vaccine was both safe and feasible to administer.
"Most patients vaccinated in this study developed strong immune responses," said Dr. Haldar. "We also gained valuable insights into the immune cell composition within patients' tumors, which could inform future therapeutic approaches for this challenging cancer type."
The study represents a significant step forward for patients with MSS mCRC, who currently have few effective treatment options after progressing on standard chemotherapy regimens.
Targeted Radiation Therapy Offers Systemic Treatment Alternative for Kidney Cancer
Systemic therapies for metastatic clear cell renal cell carcinoma (ccRCC), including immunotherapies and tyrosine kinase inhibitors, often come with significant toxicities. A team led by Drs. Chad Tang and Pavlos Msaouel conducted a Phase II prospective trial investigating whether metastasis-directed radiation therapy could provide an effective alternative.
The study enrolled 121 patients with oligometastatic ccRCC who received targeted radiation without systemic therapy. Results presented on April 28 showed a median progression-free survival (PFS) of 18 months and a median systemic therapy-free survival (STFS) of 34 months.
"Importantly, overall survival was not compromised," Dr. Tang explained. "We observed overall survival rates of 94% at two years and 87% at three years, comparable to what we would expect with standard systemic approaches but without the associated toxicities."
The researchers also evaluated a novel tumor-informed circulating tumor DNA (ctDNA) assay to detect molecular residual disease (MRD). Patients who were MRD-negative at baseline achieved a median STFS of 54 months compared to 27 months for MRD-positive patients.
"These findings demonstrate that metastasis-directed radiation therapy can help patients avoid systemic therapies without compromising outcomes," said Dr. Msaouel. "Additionally, the ctDNA assay proves to be a useful personalized prognostic biomarker for identifying patients most likely to benefit from this approach."
Engineered Exosomes Target KRAS Mutations in Pancreatic Cancer
KRAS G12D mutations occur in over 40% of pancreatic cancer cases, but existing KRAS inhibitors have not produced durable responses, partly due to the immunosuppressive tumor microenvironment.
A research team led by Drs. Valerie LeBleu, Shubham Pant, Elizabeth Shpall, and Brandon Smaglo conducted a first-in-human Phase I dose escalation trial examining engineered exosomes—small extracellular vesicles derived from bone marrow cells—designed to deliver small interfering RNA (siRNA) that silences the KRAS G12D gene in cancer cells.
The trial included 12 patients with metastatic pancreatic cancer. Results presented on April 29 showed that six of the 12 patients receiving all exosome doses achieved stable disease in target lesions, with no dose-limiting toxicities observed.
"We noted a reduction in KRAS G12D circulating DNA post-treatment, confirming the mechanism of action," said Dr. LeBleu. "Further in vivo analysis revealed that these exosomes could work synergistically with immune checkpoint blockade to reprogram the tumor microenvironment and potentially overcome treatment resistance."
Based on these promising results, the team is planning a Phase II trial investigating the combination of engineered exosomes with immune checkpoint inhibitors.
Clinical Implications and Future Directions
These three studies represent significant advances in personalized cancer treatment approaches. The NeoAg-VAX platform demonstrates the feasibility of truly individualized cancer vaccines, while the metastasis-directed radiation therapy offers a less toxic alternative for kidney cancer patients. The engineered exosome approach provides a novel method to target previously "undruggable" KRAS mutations in pancreatic cancer.
Dr. Peter Pisters, president of MD Anderson, commented, "These innovative approaches exemplify our commitment to developing more effective and less toxic cancer treatments. By targeting the specific molecular drivers of each patient's cancer, we aim to improve outcomes while maintaining quality of life."
Additional research from MD Anderson presented at AACR 2025 included early clinical trial data from the ATR kinase inhibitor ART0380 in advanced solid tumors. This targeted therapy was initially discovered and developed by MD Anderson's Therapeutics Discovery division and licensed to Artios Pharma.
The convergence of these approaches—personalized vaccines, targeted radiation, engineered delivery vehicles, and novel inhibitors—highlights the rapidly evolving landscape of precision oncology and offers new hope for patients with difficult-to-treat cancers.
