Cancer Immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Advancing Immunotherapy for Hard-to-Treat Cancers and Rare Diseases Revolutionizing T Cell Activation with Invikafusp Alfa At the Center for Immuno-Oncology (CIO) at the National Cancer Institute (NCI), we launched a first-in-human clinical trial of a new kind of immune therapy called invikafusp alfa (Hsu et al., Science Translational Medicine, 2023). This novel drug works by activating specific immune cells-T cells-with two powerful signals that drive them to attack tumors more effectively, particularly in cancers that don't respond to standard immunotherapies like PD-1 inhibitors. We first treated patients at the NIH Clinical Center and have since expanded the study across North America and Europe. The drug has been well tolerated and has shown deep, lasting responses in some patients. Based on promising results in colorectal cancer with high tumor mutation rates, the FDA granted Fast Track status in early 2025. We're now preparing a follow-up study combining this drug with existing immunotherapies to further boost its impact. Improving Immune Response in Prostate Cancer Prostate cancer has been challenging for immunotherapy. We began by testing a vaccine designed to help the immune system recognize prostate cancer cells. While the vaccine proved safe and triggered immune responses, it didn't improve survival in a large phase 3 trial. We discovered that immune cells were reaching the edge of the tumors but couldn't fully get inside-a common problem in prostate cancer. To address this, we combined the vaccine with an immune checkpoint inhibitor (a PD-1 blocker) in a new trial. In patients with localized disease, most showed a significant increase in cancer-fighting CD8 T cells inside their tumors. In advanced disease, a few patients had remarkable and long-lasting drops in PSA levels and complete disappearance of visible cancer. This suggests vaccines may make checkpoint inhibitors work better in tumors that usually resist them. The QuEST Platform: A Triple Attack We developed a novel platform called QuEST (Quick Efficacy Seeking Trial) to deliver a powerful three-part immune attack: A vaccine targeting a protein (brachyury) linked to aggressive cancers, An immune-boosting cytokine (N-803) to increase both T cell and natural killer cell activity, A dual-action antibody (bintrafusp alfa) that blocks immune suppression in tumors. This combination has shown promise in men with advanced prostate cancer. Compared to two-drug combinations, the full three-drug treatment led to more frequent and longer-lasting responses and boosted immune activation in the blood. Promising Results in HPV-Linked Cancers We also tested a new combination therapy in patients with advanced cancers caused by human papillomavirus (HPV), including cervical, anal, and head and neck cancers (Floudas et al., JAMA Oncology, 2025). This included: A vaccine (PDS0101) targeting HPV 16-an aggressive, cancer-causing virus, An interleukin-12-based immunocytokine to enhance immune cell strength, Bintrafusp alfa, the checkpoint-blocking antibody. The combination was safe and highly effective-especially in patients whose tumors were HPV 16-positive and who hadn't received prior immunotherapy. Nearly all of these patients saw significant tumor shrinkage, far exceeding typical response rates with standard immune therapies. A Breakthrough for a Rare Disease: Recurrent Respiratory Papillomatosis (RRP) In a major step forward for a rare, non-cancerous disease called recurrent respiratory papillomatosis (RRP)-which causes benign tumors in the airway and often requires repeated surgery-we led a first-of-its-kind clinical trial of a new therapeutic vaccine called PRGN-2012. This vaccine targets the HPV 6 and 11 viruses responsible for the disease. In our NIH study, over half of the patients stayed surgery-free for more than a year after just one 3-month treatment. Based on this success, a rolling application for FDA approval was submitted in December 2024, and a final decision is expected by August 27, 2025. We are leading the national phase 3 confirmatory study to bring this option to more patients. Cellular Therapy: Innovations in Engineering and Clinical Application As part of our cellular therapy efforts, we are leading multiple pre-clinical and clinical projects. One pre-clinical project focuses on T cell receptor (TCR) T cells engineered to express membrane-anchored interleukin-12 (ma-IL12). By anchoring IL12 to the surface of T cells, we reduce toxicity while preserving anti-tumor effects. In our publication (Zhang L et al., JITC 2024), we showed that ma-IL12-expressing TCR-T cells not only killed antigen-positive cancer cells but also activated the patient's own CD8 T cells to target cancer variants lacking the antigen. This has the potential to overcome antigen escape and tumor heterogeneity-major challenges in solid tumor treatment. A second pre-clinical project investigates TIL engineered to express a mutant form of CD3 zeta, a key T cell signaling molecule. In preclinical studies, this modification enhances tumor-killing ability, especially for T cells with lower affinity receptors-common in patient-derived TIL products. This research, conducted under a Cooperative Research and Development Agreement (CRADA) with a biotech startup, may lead to a new clinical trial of CD3 zeta-engineered TIL in advanced cancer. We are also advancing the use of liquid biopsies as predictive tools in cellular therapy. Genetic changes such as human leukocyte antigen (HLA) loss of heterozygosity and defects in antigen processing pathways can lead to treatment resistance. Liquid biopsies offer a non-invasive and cost-effective method to detect these changes. This project received both the 2024 Federal Technology Transfer Award and the 2024 NCI Director's Award for Translational Science, and has led to the formation of a startup, Sesh Inc. Among clinical projects, we are studying a TCR-T therapy targeting HPV16 E7 in HPV-related cancers. Initially developed at NCI, the therapy showed safety and early activity in a first-in-human trial. We have partnered with Dr. Christian Hinrichs at Rutgers Cancer Institute to run a phase 2 trial (NCT05686226) using next-generation manufacturing and genomic screening to identify patients most likely to benefit. This study is funded by a U01 Grant. Another clinical study targets KK-LC-1, a cancer germline antigen. Developed at NCI, this TCR-T therapy is now in a multi-center phase 1 trial (NCT05035407) in collaboration with Rutgers, using a decentralized manufacturing model. Finally, we are addressing an important gap in care for people with HIV (PWH). Despite the success of adoptive T cell therapy (ACT) in many cancers, PWH are often excluded from trials. We created a novel TCR-T cell manufacturing method that limits HIV replication while preserving anti-tumor function. We received a 2023 CCR FLEX Award and are developing a phase 1/2 trial for this approach.