One-third of HER2-positive (HER2+) tumors express the P95HER2 protein, which associates with an aggressive form of breast cancer with a poorer prognosis. Investigators of the Vall d'Hebron Institute of Oncology's (VHIO) Growth Factors Group, in collaboration with researchers of the Cancer Research Program of Hospital del Mar Research Institute (HMRI), Barcelona, have developed novel chimeric antigen receptor (CAR) T-cell therapy that can produce a potent antitumor response against p95HER2-expressing cells.
This novel approach consists of T cells engineered to express a CAR against p95HER2 and secrete the TECH2Me bispecific antibody that specifically recognizes tumor cells. In addition, this bispecific antibody activates immune cells within the tumor microenvironment (TME). This new therapeutic strategy has been evaluated in patient-derived models of HER2+ P95HER2-expressing solid tumors.
Preclinical findings from this present study, published today in Nature Communications*, show safety as well as complete and durable antitumor responses in a subset of HER2+ tumors. Based on these promising results, a first-in-human phase 1 clinical trial is currently in the approval process for evaluating this novel therapy in patients with HER2-overexpressing tumors.
The Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer), through the company AUSONIA, has supported this research since 2019 as part of a project focused on developing new therapeutic strategies against HER2-positive breast cancer, which is coordinated by Joaquín Arribas, an ICREA Research Professor, Head of VHIO's Growth Factors Group, HMRI's Director and corresponding author of this present study. Arribas' laboratory has received funding from the Breast Cancer Research Foundation (BCRF) since 2007.
CAR T-cell therapy: rapidly evolving as a new pillar of cancer treatment
CAR T-cell therapy is a type of adoptive cell transfer that involves genetically modifying a patient's T-cell lymphocytes to become CAR T-cells. Grown and multiplied in the laboratory, these cells are then reintroduced into the patient's bloodstream to recognize and attack specific cancer cells.
"This type of advanced cell therapy has shown significant efficacy in various hematologic cancers. Despite its successes, CAR T-cell therapy faces challenges as treatment for solid tumors," said Joaquín Arribas.
Tumors driven by HER2 overexpression
In normal amounts, HER2 plays a crucial role in epithelial cell proliferation, survival, and differentiation. HER2 overexpression is linked to aggressive tumor growth, a poorer prognosis, and reduced response to some conventional therapies, making it a highly sensitive target for cancer treatment. HER2 is overexpressed and gene amplified in an estimated 4% of tumors and in about 15% of breast cancers, one third of which also express p95HER2-an altered form of the HER2 receptor-which correlates with more aggressive disease.
"HER2 is arguably the most targeted receptor in the development of cancer therapies, especially in breast or gastric cancer. While several different therapies have been developed to treat HER2-positive tumors, an important number of people with these cancers, and up to one third of patients with advanced-stage HER2-positive breast cancer, do not respond to these treatments," observed Arribas.
As part of the Fundación BBVA CAIMI Program, research led by VHIO's Growth Factors Group focuses on advancing new therapies designed to unleash and boost the immune system against HER2-driven tumors.
p95HER2 tumor-specific antigen
Over recent years, Arribas and his team have generated an antibody against p95HER2. Using specific antibodies, the investigators showed that this protein, unlike HER2, is a bona fide tumor specific antigen and is not expressed in normal tissues. They have also developed a second-generation CAR T-cell therapy, both targeting p95HER2. To increase the efficacy of these CAR T cells they also engineered these CART cells to secrete bispecific antibodies against overexpressed HER2. While both approaches demonstrated efficacy and safety in cell lines of HER2+ breast cancer, they failed to achieve durable responses in animal models.
"The development of cell therapies such as CAR-T in solid tumors requires new strategies that further enhance a patient's immune response against cancer. We decided to generate a state-of-the-art CAR-T, loaded with additional therapeutic components that could effectively, durably, and safely enhance the anti-tumor immune responses," said Macarena Román, a postdoctoral researcher of VHIO's Growth Factors Group and first author of this present study.
Next-generation CAR-T
The researchers loaded CAR-T with a p95HER2 receptor and CAR-T activator and evaluated if this CAR-T could secrete the TECH2Me small bispecific BiTE® antibody with an affinity attenuated by the overexpression of HER2 to avoid toxicities in healthy cells with normal levels of HER2 and, at the same time, activate all types of T cells, including CAR T-cells and other immune cells present in the TME.
"Using in vitro and in vivo models, we observed that this new CAR-T achieved safe, complete and durable responses. Using patient-derived xenograft models of HER2+ P95HER2-expressing breast cancer, we found that in most mice, tumors of considerable size shrank until they completely disappeared. These mice lived for months without an observed effect on their quality of life," added Román.
"We have seen very promising responses, but these preclinical findings will of course need to be validated in a phase 1 clinical trial to firstly confirm the safety of this approach, with further investigations required to corroborate efficacy data. VHIO has already secured the funding and submitted an application for the initiation of the clinical study to evaluate the safety of this next-generation CAR-T therapy in patients," concluded Arribas.
Upon successful completion of the application process, this trial is envisaged to start next year. Supported by the AECC and the Instituto de Salud Carlos III - ISCIII (Institute of Health Carlos III), this study has been designed to include fifteen patients with HER2-driven tumors who have exhausted all available therapeutic options. Further evaluations and development of this therapeutic approach could represent a promising strategy to improve outcomes in a subset of patients with HER2+ tumors.
This work is part of the Immune-Image European consortium. Supported by the Innovative Medicines Initiative 2 Joint Undertaking, the European Union's Horizon 2020 research and innovation programme and EFPIA, it consists of 21 key stakeholders from across 9 countries, including VHIO. The overarching objective of this project is to develop a novel non-invasive imaging strategy for assessing immune cell activation and dynamics in oncology and inflammatory disease, in animal models and in patients.
