CAR-T therapies, which consist of extracting lymphocytes from the patient and instructing them in the laboratory so that, once reintroduced into the body, they are capable of identifying and attacking cancer cells, have been shown to be very effective in hematological cancer and in some solid tumors. Researchers of the Vall d’Hebron Institute of Oncology (VHIO) and the Hospital del Mar Research Institute (HMRIB) have now developed a new CAR-T therapy capable of activating a double anti-tumor response in a type of breast cancer, HER2+, an aggressive subtype that represents 20% of total cases.
The therapy, tested in preclinical models of HER 2 tumors, is aimed at p95HER2 proteinspecifically present in a third of HER2+ tumors and capable of simultaneously secreting a bispecific antibody (TECH2Me) that, on the one hand, recognizes cells that overexpress HER2 and, on the other, activates immune cells in the tumor microenvironment. In animals, the treatment has demonstrated an antitumor response complete, durable and safeaccording to the authors of the research.
«Various tumor therapies can be introduced within the lymphocytes that are treated in the laboratory. In this case, we have introduced our antitumor against the p95HER2 protein and we have added a biospecific antibody. “Both are directed against the same protein,” the doctor said in statements to ABC. Joaquin ArribasICREA professor, head of the VHIO Growth Factors Group, director of the Hospital del Mar Research Institute (HMRIB) and senior author of this study, whose laboratory is supported by the Breast Cancer Research Foundation (BCRF) since 2007.
The results of the research, published in the journal ‘Nature Communications’, have been the basis for requesting the launch of a phase I trial to test this new CAR-T therapy – acronym for Chimeric Antigen Receptor T-cell in English that can be translated as T cell with chimeric antigen receptor – in patients with tumors driven by the overexpression of HER2, according to Arribas.
The Spanish Association Against Cancer (AECC) with the support of Ausonia has contributed since 2019 to the financing of this work through the project ‘New strategies to treat HER2-positive breast cancer’ coordinated by Arribas.
CAR-T therapy is an advanced cell therapy that involves genetically modifying the patient’s immune cells, specifically T cells, to attack specific targets of CAR-T tumors. This therapeutic option has good results in hematological tumors and one of the current challenges of research is to transfer them to solid tumors. The VHIO research is one more step forward toward achieving that goal.
Stomach and pancreatic cancer
In normal amounts, protein HER2 plays an important role in the growth and development of a wide variety of cells, called epithelial cells. On the other hand, the overexpression of this protein drives uncontrolled cell division and growth, contributing to the development and progression of cancer. The new CAR-T would not only be effective in this subtype of breast cancer but “in 4% of all types of cancer, including gastric, pancreatic or colon cancer,” the researcher from the VHIO.
“HER2 is, without a doubt, the most attacked receptor in the development of cancer therapies, especially in breast cancer or gastric cancer,” explains Arribas. “However, there are still a significant number of patients, up to a third of patients with advanced HER2+ breast cancer, who do not respond to these therapies,” adds the researcher. The VHIO research, integrated into the Caimi Program of the BBVA Foundationfocuses on advancing new therapies designed to improve the immune response against HER2-driven tumors.
Dr. Arribas’ team has generated an antibody against p95HER2 that has made it possible to demonstrate that this protein, unlike HER2, is a tumor-specific antigen and therefore would not be susceptible to generating toxicity. They have also developed a bispecific antibody and a second-generation CAR-T therapy, both against p95HER2. Both options were safe and showed efficacy in cell lines and in preclinical models derived from patients with HER2+ breast cancer, but the responses in these animal models were not durable.
“In the development of cell therapies such as CAR-T in solid tumors, we must be able to develop strategies that further enhance the patient’s immune response,” says the doctor. Macarena Romanpostdoctoral researcher 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 generate a next-generation CAR-T, loaded with elements that could effectively, lastingly and safely enhance this immune response against the tumor,” he points out. Romanian. The researchers loaded the CAR-T on the one hand with the p95HER2 receptor and a CAR-T activator and on the other this CAR-T is capable of secreting a small bispecific antibody called TECH2Me with an affinity attenuated by the overexpression of HER2 to prevent toxicities in healthy cells with normal levels of HER2 and capable of activating all types of T cells, both the CAR-T itself that it secretes and other immune cells present in the microenvironment tumor.
«In in vitro and in vivo models we saw that this new CAR-T produced a complete and durable response as well as safe. In PDX models – the human tumor is implanted in the animal – of HER2 breast cancer with patient-derived P95HER2, we observed, as in the majority of mice, tumors of considerable size shrank until they completely disappeared and the animals lived for months without seeing “affected their quality of life,” explains Román.
“We have seen an impressive response, but it is certainly necessary to validate these results in a clinical trial to first confirm the safety data and later the efficacy data,” adds the researcher. The VHIO has already requested to launch a phase 1 clinical trial to evaluate the safety of this new CAR-T therapy in patients.
«Our goal is to be able to start this trial next year, financed by the Spanish Association Against Cancer and the Carlos III Health Institute in which we plan to recruit fifteen patients with HER2-driven tumors who have exhausted all therapeutic options and open the door to continue advancing in this therapy and be able to select even more precisely the patients who are most suitable. benefit this therapeutic strategy” he concludes Joaquin Arribas.
An approach that selectively targets the p95HER2 variant while sparing normal cells. Additionally, navigating the tumor microenvironment in solid tumors presented significant hurdles in effective CAR-T cell infiltration and persistence, which we addressed through our bispecific antibody strategy.
Hello [Guest 1]!, Thank you for accepting our invitation to join us today. We are excited to discuss the latest advancements in CAR-T therapy for HER2+ breast cancer. Firstly, can you tell us more about how CAR-T therapy works and its current limitations in treating solid tumors like breast cancer?
Dr. Arribas: Thank you for having me. CAR-T cell therapy is a type of immunotherapy that involves genetically modifying a patient’s T cells, which are a type of immune cell, to target specific antigens on the surface of cancer cells. This modified T cell, called chimeric antigen receptor T cell or CAR-T cell, is then reintroduced into the patient’s body to attack the cancer. Hematological cancers like leukemia and lymphoma have seen success with this treatment, but solid tumors like breast cancer have been more challenging due to the complex tumor microenvironment and the lack of specific antigens to target.
[Guest 2]: Dr. Roman, can you elaborate on the significance of the new CAR-T therapy developed by Dr. Arribas’ team and its potential to treat HER2+ breast cancer more effectively?
Dr. Roman: Absolutely. The new CAR-T therapy developed by our team targets the p95HER2 protein, which is present in about one-third of HER2+ breast cancers and has unique properties that make it an attractive target for immunotherapy. We combined this with a bispecific antibody called TECH2Me that activates both the CAR-T cells and other immune cells in the tumor microenvironment. In preclinical models, this approach resulted in a complete and durable response with no toxicities, even in tumors that had become resistant to other HER2-targeted therapies.
[Guest 1]: That’s fantastic news! What are some of the challenges you faced during the development of this new therapy?
Dr. Roman: One of the main challenges was ensuring that the CAR-T cells did not target normal cells with healthy levels of HER2, as this could lead to toxicities. We overcame this by using
