UCLA Immunotherapy Research: Pioneering Advances in Cancer Treatment
Ovarian cancer remains a major cause of death among women with gynecological cancers, and while initial treatments like surgery and chemotherapy can shrink or eliminate tumors, recurrence is common. UCLA researchers are at the forefront of developing innovative immunotherapies to combat cancer, including ovarian cancer, kidney cancer, and melanoma, with the goal of improving patient outcomes and survival rates. The UCLA Health Jonsson Comprehensive Cancer Center's Tumor Immunology & Immunotherapy (TII) research program plays a vital role in this effort, fostering an environment focused on understanding tumor immunology and developing new immunotherapies for cancer. This article delves into some of the groundbreaking immunotherapy research underway at UCLA, highlighting novel approaches and promising clinical trial results.
Tumor Immunology & Immunotherapy (TII) Research Program at UCLA
The TII research program at UCLA is dedicated to enhancing the understanding of tumor immunology and developing new immunotherapies for cancer. This involves studying fundamental biological processes and applying these insights to create immune-modulating agents and genetically engineered adoptive-cell-transfer therapies. The program fosters interdisciplinary collaborations and supports a systematic approach to developing next-generation cancer immunotherapies, facilitating the clinical translation of novel treatment strategies and in-depth analyses of patient-derived samples to further understand the mechanistic basis of response and resistance to therapies.
The TII research program brings together basic and translational scientists, fostering an environment that has led to novel investigator-initiated immunotherapy clinical trials and the approval of immune checkpoint inhibitor therapies for a broad range of tumor types. The program's basic science focuses on the genetic engineering of immune-cell responses to cancer and understanding the interplay between the immune system and cancer, including the biology of immune responses to cancer and the relationship between inflammation and cancer. Research areas include the use of antibody fusion proteins for cancer therapy and their combination with targeted therapies to sensitize cancer cells to immunotherapy, and improving the lives of patients with AIDS-related cancers.
The principal objective of the TII Research Program is to support and expand the pipeline of novel immunotherapies from bench to bedside, to benefit cancer patients in the JCCC Los Angeles County catchment area and beyond. The Program’s specific aims are to enhance understanding of tumor immunology and the tumor microenvironment, and their responses to different modalities of cancer immunotherapy and to develop novel immune-based clinical therapies for patients with cancer to favorably impact the community served by the UCLA Health JCCC.
The TII Research Program is led by Dr. Antoni Ribas, a professor of medicine, surgery, and molecular and medical pharmacology at UCLA. Dr. Ribas conducts laboratory and clinical research in malignant melanoma, focusing on gene-engineered T cells, PD-1 blockade, and BRAF targeted therapies. His research laboratory develops models of disease to test new therapeutic options, studies the mechanisms of action of treatments in patients, and investigates the molecular mechanisms of therapy resistance. He also directs the Parker Institute for Cancer Immunotherapy Center at UCLA, coordinating the research of five funded laboratories aimed at advancing new immunotherapies for cancer. Co-director Yvonne Chen is an associate professor of microbiology, immunology, and molecular genetics. Her laboratory focuses on applying synthetic biology and biomolecular engineering techniques to the development of novel mammalian cell systems, particularly T-cell therapy for cancer.
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Novel CAR-NKT Cell Therapy for Ovarian Cancer
CAR-T cell therapies have demonstrated success in treating blood cancers by genetically engineering patients' immune cells into cancer-fighting agents. However, UCLA researchers are exploring new approaches to overcome the challenges of treating solid tumors like ovarian cancer. One promising strategy involves CAR-NKT cells, which are engineered to target multiple targets on cancer cells.
Yang’s team has developed a scalable strategy to mass-produce these cells from donated blood stem cells. This multi-target approach addresses a critical problem: the cat-and-mouse game between cancer and treatment. “Cancer is like a moving target because it’s constantly changing and adapting,” said first author Yanruide (Charlie) Li, a postdoctoral scholar in the UCLA Broad Stem Cell Research Center Training Program. That's exactly what these engineered CAR-NKT cells do. The CAR-NKT approach addresses these bottlenecks through a fundamentally different manufacturing method.
When the team tested the novel CAR-NKT therapy on 35 ovarian patient-derived tumor samples, the results were striking. “Combating this high rate of recurrence in ovarian cancer is my career mission,” said co-senior author Memarzadeh, a professor of obstetrics and gynecology and a member of the UCLA Broad Stem Cell Research Center and the UCLA Health Jonsson Comprehensive Cancer Center. “This is the culmination of over a decade of work in my lab and represents over six years of collaboration with gynecologic oncologist Dr. Lili Yang and Dr. Yang said.
Although ovarian cancer is their initial focus, this advancement could have much broader applications.
AlloCAR70-NKT: An "Off-the-Shelf" Immunotherapy for Kidney Cancer
UCLA researchers have also developed a new kind of immunotherapy for kidney cancer that uses specially engineered immune cells equipped with built-in weapons to attack tumors and reprogram their protective environment, all without the need to customize treatment for each individual patient. This “off-the-shelf” approach, called AlloCAR70-NKT, could improve outcomes, reduce complications, and expand access for patients with limited treatment options.
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“We successfully turned stem cells into powerful cancer-fighting immune cells that can be ready to use for any patient, bypassing the need to engineer each patient’s own cells,” said Dr. Lily Wu, professor of molecular and medical pharmacology and urology at the David Geffen School of Medicine at UCLA and co-senior author of the study. “This approach overcomes the time delays and safety risks of traditional immunotherapies, especially for patients with aggressive, late-stage disease.”
To address these challenges, researchers at the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research developed AlloCAR70-NKT, an innovative cell therapy that harnesses the body’s immune system to fight cancer more effectively. In the study, published in Cell Reports Medicine, researchers created the therapy by genetically engineering natural killer T (NKT) cells derived from stem cells to express a chimeric antigen receptor (CAR) that targets CD70, a protein commonly found on kidney cancer cells. These AlloCAR70-NKT cells were designed to resist immune rejection and remain active in the tumor environment.
“This approach tackles a challenge in cancer immunotherapy: developing an off-the-shelf cell therapy that can persist and function effectively in patients without causing serious immune complications,” said Dr. Lili Yang, professor of microbiology, immunology and molecular genetics at UCLA and co-senior author of the study.
When tested in preclinical models, AlloCAR70-NKT cells demonstrated a multi-pronged attack against kidney cancer. First, the cells directly killed cancer cells through both the engineered CAR and their NKT receptors, even when the tumors had low levels of the CD70 protein, which usually makes them harder to treat. Second, they disrupted the tumor’s microenvironment, a protective barrier made up of suppressive immune cells that typically shields the tumor from immune attack, which often helps cancer resist treatment. Third, they eliminated CD70-positive host immune cells that would normally reject the donor cells, allowing the therapy to persist longer in the body and sustain its anti-tumor activity. Since these cells don’t remain in the body indefinitely, they are less likely to cause long-term immune system problems, such as chronic immune suppression or graft-versus-host disease.
“This multi-pronged approach helps them attack both the tumor and its surrounding support system, making them a potent, multifunctional and safer immunotherapy option for metastatic kidney cancer,” said Dr. Arnold Chin, professor of urology at the David Geffen School of Medicine at UCLA and co-senior author of the study. “If the early promise translates to patients, it could offer a new lifeline for many.”
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Pembrolizumab for Desmoplastic Melanoma
A research team co-led by UCLA investigators has found that pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, can effectively shrink or eliminate tumors in patients with unresectable advanced desmoplastic melanoma, a rare and often aggressive form of skin cancer.
The study, published in Nature Medicine, showed that nearly 90% of participants experienced significant tumor reduction or complete disappearance after receiving pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, highlighting the therapy as a promising treatment option for this difficult-to-treat cancer.
“Patients with advanced desmoplastic melanoma demonstrate a high response rate to single-agent PD-1 blockade therapy, reinforcing the use of anti-PD-1 as the preferred treatment option for this disease,” said Dr. Antoni Ribas, the study’s senior author, a professor of medicine at the David Geffen School of Medicine at UCLA and director of the UCLA Health Jonsson Comprehensive Cancer Center’s Tumor Immunology Program. “It offers a less invasive, more targeted approach compared to surgery, radiation or combination immunotherapies, which can have more severe side effects.”
The team found that 37% of patients had a complete response, meaning their tumors completely disappeared. Overall, 89% of patients experienced tumor shrinkage or disappearance. Importantly, the responses were often rapid, with some patients seeing tumor reduction within two months. Many maintained their remission long after stopping treatment. After three years, 84% of patients were still alive, and 72% showed no signs of cancer progression.
Targeting Adenosine in Pancreatic Cancer
Investigators from the UCLA Health Jonsson Comprehensive Cancer Center were awarded a $4 million grant from the National Cancer Institute to help advance immune-based therapies to improve treatments and outcomes for people diagnosed with pancreatic ductal adenocarcinoma, one of the most aggressive and deadly forms of cancer.
By understanding how adenosine affects the tumor environment and interactions between cancer and immune cells, the researchers hope to find new therapies that target adenosine to improve treatments and outcomes for people with pancreatic cancer, ultimately aiming to enhance health and reduce the burden of the disease.
The funding will also help support a follow-up phase 1/2 clinical trial that will examine a small molecule inhibitor with the existing combination of PD-1, an immunotherapy drug, and chemotherapy before surgery. The recent 1A/1B trial, which evaluated just the PD-1 and chemotherapy combination, showed promising results, but the team found an increased adenosine signaling in post-treatment tumors that posed a significant challenge to sustained anti-tumor immunity.
“By introducing a small molecule inhibitor of to the existing chemotherapy and PD-1 inhibition regimen, we hope to limit adenosine production in the tumor microenvironment, thereby enhancing the immune response against the cancer,” said Donahue.
California Institute of Immunology and Immunotherapy (CIII) at UCLA Research Park
On January 4, 2024, the California Institute of Immunology and Immunotherapy (CIII) celebrated the establishment of its future home at UCLA Research Park in Los Angeles. CIII will become a hub of innovation and the world’s leading center for decoding the human immune system. The pioneering research center, uniquely combining quantum computing, artificial intelligence, and biomedical research, holds immense potential to revolutionize how we treat diseases and solve global climate challenges. A range of researchers and investigators will pursue their discoveries and innovations at CIII to make profound, lifesaving advancements in the landscape of immunological research, medical innovation, and human health.
Dr. Antoni Ribas: A Pioneer in Immunotherapy
Dr. Antoni Ribas develops groundbreaking immunotherapies and interventions that mobilize the immune system to fight cancer. By studying the cellular mechanisms driving-or inhibiting-an immune response to cancer, Dr. Ribas has made significant contributions to the field.
He found that pembrolizumab-a drug developed by Merck to block PD-1-helped many patients fight their cancer. However, PD-1 blockade did not help all patients, and Dr. Ribas wanted to know why. Pembrolizimab worked best when T cells had flocked to the tumor site, giving PD-1 blockade plenty of “fighters” to release. Pembrolizimab failed when T cells ignored the tumor site, leaving PD-1 blockade with no “fighters” to release.
Dr. Ribas combined pembrolizumab with an oncolytic virus, injected at the tumor site. He believed the virus-a foreign invader-would lure T cells toward cancer tumors and boost the efficacy of PD-1 blockade. The combined therapy increased T cells at tumor sites and stimulated a complete response in 33% of patients.
With his sights set on optimizing cancer immunotherapy, Dr. Ribas plans to learn as much as he can by testing new treatments, including adoptive cell transfer therapy, and investigating the underlying immune system mechanisms that render treatments effective or ineffective. Dr. Ribas wants to uncover the limits and potentials of the human immune system in the fight against cancer, a pursuit rooted in scientific understanding.
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