He VHIO Growth Factor Group And Hospital del Mar Research Institute (HMRIB) developed innovative therapy based in CAR-T cellscapable of inducing a strong antitumor response against cells that p95HER2 protein. This protein is found in a third of HER2+ tumors, and in addition, the therapy can secrete a bispecific antibody that identifies cells overexpressing HER2, activating both CAR-T and other immune cells present in the tumor microenvironment.
This new generation of CAR-T has been evaluated in preclinical models of HER2+ tumors expressing p95HER2 obtained from patients. The results show a complete, durable and safe antitumor response. In addition, the results, published today in the journal Nature Communications, prompted a request for a phase I clinical trial to test this therapy in patients with tumors driven by HER2 overexpression.
Since 2019, the Spanish Cancer Association, with the support of Ausonia, has been funding this research as part of the project “New treatment strategies for HER2-positive breast cancer”, coordinated Dr. Joaquin Arribas
Professor at ICREA, Head of the VHIO Growth Factors Group and Director of the Hospital del Mar Research Institute (HMRI). In addition, his laboratory has been supported by the Breast Cancer Research Foundation (BCRF) since 2007.Under normal conditions, the HER2 protein plays a critical role in the development and growth of epithelial cells. However, its overexpression causes uncontrolled cell proliferationcontributing to the development and progression of cancer. It is estimated that 4% of tumors overexpress HER2, and in breast cancer this figure rises to 15%. More than a third of these tumors also have an altered variant known as p95HER2, which is associated with greater aggressiveness.
“HER2 is without a doubt the most studied receptor in the development of cancer treatments, especially breast and gastric cancer.”
“HER2 is without a doubt the most studied receptor in the development of cancer treatments, especially breast and gastric cancer,” says Dr. Joaquín Arribas. “Although many treatments have been developed for these tumor types, there is still a significant percentage of patients, up to a third of people with advanced HER2+ breast cancer, who do not respond to these treatments.”
As part of the BBVA Foundation’s CAIMI program, the VHIO growth factor group’s research is focused on advancing new treatments that enhance the immune response against HER2-driven tumors.
PROTEIN FUNCTIONING AS A SPECIFIC TUMOR ANTIGEN
In recent years, this group has developed an antibody against p95HER2, demonstrating that this protein, unlike HER2, is a tumor-specific antigen and does not cause toxicity. They also created a bispecific antibody and second-generation CAR-T therapy targeting p95HER2. Although these strategies have shown safety and efficacy in HER2+ breast cancer cell lines and PDX models, responses in these models were not durable.
“For cell therapies such as CAR-T in solid tumors, we must develop strategies that enhance the patient’s immune response,” points out Dr. Macarena Romanresearcher at the VHIO Growth Factors Group and the Hospital del Mar Research Institute and first author of the study. “For this reason, we decided to create the next generation of CAR-T, equipped with tools capable of enhancing an effective, long-lasting and safe immune response against the tumor,” he adds.
COMPLETE AND RELIABLE CAR-T ANSWER
Researchers have developed this CAR-T with p95HER2 receptor and activatedr and also gives it the ability to secrete a bispecific BiTE antibody called TECH2Me. This antibody has moderate affinity for HER2, avoiding toxicity to healthy cells, and can activate both CAR-T cells and other T cells in the tumor microenvironment.
“In in vitro and in vivo models, we observed that this new CAR-T produced a complete, durable and safe response. In patient-derived PDX models of HER2+ breast cancer with p95HER2, we saw how in most mice, the tumors shrank until they disappeared.which allows animals to live for months with a good quality of life,” explains Dr. Roman. “We have seen promising results, but it is important to validate these data in clinical trials to confirm safety and therefore effectiveness.”
“We plan to recruit approximately fifteen patients with HER2-driven tumors who have exhausted all available options, opening the door to future advances in this therapy and more precise selection of patients who may benefit from it.”
VHIO has already requested permission to conduct the first phase of clinical trials. evaluate the safety of this therapy in patients. “Our goal is to start the study next year with financial support from the Spanish Cancer Association and the Carlos III Institute of Health. We plan to recruit fifteen patients with HER2 tumors who have exhausted all available options, opening the door to future advances in this therapy and a more precise selection of patients who may benefit from it,” concludes Dr. Joaquín Arribas.
This study is part of the European Immune Image Consortium, in which VHIO participates. This project aims to develop and implement a non-invasive molecular imaging platform to study immune cell activation and dynamics in cancer and inflammatory diseases in both animal models and patients.