Hematologic malignancies, including leukemia, lymphoma and myeloma, represent about 10% of all cancers and affect people of all ages. About 50% of HM are resistant to chemotherapy. Patients who cannot be cured by standard chemotherapy can sometimes be cured by allogeneic hematopoietic cell transplantation (AHCT). However, a cure is only possible for some patients. If we consider patients with acute myeloid leukemia in particular, with current treatment regimens, 65%–70% of patients will reach a complete remission after induction therapy. If an ASCT is done during first remission, the 5-year disease-free survival rate is only 30%–50%. SpecificiT’s goal is to significantly reduce the rate of leukemia relapse post transplantation.
Cure by AHCT when it is achieved through an immune reaction called the allogeneic graft-versus-tumor effect (GVTE). GVTE occurs when T-cells have an immune response against host MiHAs found on the surface of malignant cells. Even when patients and donors are matched for their major histocompatibility alleles (HLA types), differences still exist between the donor and the patient in the form of MiHAs. When these antigens are expressed on malignant cells, it can elicit GVTE. However, MiHAs expressed on other tissues can trigger a potentially lethal graft-versus-host-disease (GVHD) reaction.
SpecificiT is aiming to harness the potency of MiHAs found on the surface of malignant cells to elicit strong GVTE without the risk of GVHD.
Adoptive T-cell immunotherapy refers to the injection of mature T cells after minimal or extensive ex–vivo manipulations and is a recognized treatment for relapse of leukemia following AHCT. Upon relapse of leukemia following AHCT, patients can be treated with donor lymphocyte infusions (DLI) from their stem cell donor in order to improve the remission profile (i.e. augment an anti-tumor immune response or ensure that the donor stem cells remain engrafted). However, in patients with relapsed AML, MDS or myelomas, only 10-30% of patients achieve remission after DLI because the immune response is too weak.
SpecificiT aims to create a safer and more effective allogenic immunotherapy. Dr. Claude Perreault and his colleagues used an advanced proteogenomic platform to identify a unique and comprehensive proprietary library of 100 MiHAs expressed mainly, or only in hematopoietic cells, and overexpressed on leukemic cells. This library is being used to manufacture T-cells that specifically recognize leukemic cells and do not attack other tissues. Donor T-cells are transferred into hematologic cancer patients to eliminate cancer cells without weakening their immune system.
SpecificiT’s proprietary MiHAs peptide library allows for the manufacture of Guided Lymphocyte Immunopeptide Derived Expansion (GLIDE), the ex vivo generation and expansion of donor T-cell lines that specifically recognize MiHAs expressed by the patient’s leukemic cells. Exome sequencing is used to ensure that the selected antigens are only present on the patient’s leukemic cells and not present on the donor cells, ensuring that they are recognized as “foreign” by the donor’s immune cells.
CAR-T cells are re-engineered T-cells that are capable of recognizing self-antigens. When CAR-T is directed against the B-lymphocyte antigen CD19, it has been shown to induce complete responses in patients with refractory B-cell hematological malignancies, but destroys normal B cells as well resulting in B cell aplasia (low numbers of B cells or absent B cells). B cell aplasia results in a lowered ability to make antibodies that protect against infection. Although this immune weakening can be managed by monthly injections of gamma immunoglobulin, this is not a feasible option when targeting other surface markers.
CD19 is perhaps one of the few self-antigens that can be safely targeted with CAR-T because it is expressed on a cell lineage that is not essential for survival. However, directing CAR-T against myeloid surface markers would lead to a lethal reduction in the number of blood cells (cytopenia).
SpecificiT’s GLIDE approach does not have this limitation as it does not result in the elimination of normal cells. Moreover, the allogeneic hematopoietic cell transplantation (AHCT) makes the patient’s blood cells identical to the donor and therefore is unlikely to induce cytopenia as T-cells will not mistake the patient’s blood cells as foreign.