We have a strong focus on understanding the molecular and cellular mechanisms of cancer immune escape, and on the development of new immunoengineering approaches for cancer immunotherapy.
The “escape” is the final phase of cancer immunoediting process, and many molecular and cellular events are responsible for the evasion of cancer cells from the host immune system. Tumors undergo continuous remodeling at the genetic, epigenetic and metabolic level to acquire resistance, and at the same time, it induces accumulation of immunosuppressive factors and cells to elude the attack of the immune system.
New immunoengineering approaches are being developed to block the different events involved in cancer escape, with the aim of achieving maximum therapeutic efficacy with minimal toxicity.
Specific research focus includes: molecular and cell engineering for cancer immunotherapy.
The emergence of recombinant technologies has revolutionized the selection and production of monoclonal antibodies, allowing the design of fully human antibodies that are well tolerated and have achieved remarkable clinical success. However, conventional IgG-based antibodies face some limitations, including mechanisms of action and inadequate pharmacokinetic and tumor accessibility.
One of the most active research areas in our group is the development of next-generation bispecific antibodies. Redirecting the activity of T cells using bispecific antibodies, which cross-link tumor cells and T cells, independently of their T cell receptor specificity, is a potent cancer immunotherapy. The core concept of this approach is an antibody’s binding to a cell surface tumor-associated antigen (TAA) and simultaneous binding to the CD3 on the surface of T lymphocytes. This crosslinking activates the T cell, resulting in secretion of cytokines and cytotoxic effector proteins, which induces cancer cell killing.
Chimeric antigen receptors (CARs) are synthetic receptors recognizing user-defined cell surface TAAs that are not associated to major histocompatibility complex (MHC) molecules. For this reason, genetically engineered T cells expressing a TAA-specific CAR (CAR T cells) are applicable to all patients regardless of their MHC haplotype, and circumvent the problem of tumor scape by MHC down-regulation. CARs are modular molecules consisting of an extracellular antigen-binding domain, a transmembrane domain and an intracellular signaling domain. The addition of a costimulatory domain (CD28 or 41BB) in second-generation CAR constructs enables improved T cell activation and proliferation, cytokine secretion, and most notably impressive antitumor responses in patients with hematologic cancers. Several anti-CD19 CAR T cell therapies have been approved for the treatment of B cell precursor acute lymphoblastic leukemia and relapsed or refractory large B-cell lymphomas.
Solid tumors present additional challenges, given that the tumor environment is highly immunosuppressive, and the majority of TAAs are also expressed on normal tissues, which cause the appearance of on-target/off-tumor toxicity.
Some of the limitations indicated above could be solved by secreting T cell-redirecting bispecific antibodies in vivo in the patients. In vivo secretion might result in effective and persistent levels of the antibody and could compensate for the rapid blood-pool clearance and make the antibodies better tolerated. Several projects are currently under development to bring this approach to the Clinic.