Hematologic cancers (HCs) represent about 10% of all cancers and the lifetime risk of developing an HC is 5%. The number of new cases of HCs in Canada is 16,000/year (incidence), and no measures can be taken to prevent these cancers. Currently, 67,000 living Canadians have been diagnosed with an HC over the last ten years (prevalence). While about 50% of patients with HC can be cured by chemotherapy, 50% develop resistance to chemotherapy and eventually die. HC affects adults and children, accounting for 60,000 potential years of life lost in Canada per year only. The ultimate objective of the proposed project is to provide safer and more effective treatments for patients with chemotherapy resistant HCs.
For these patients, allogeneic hematopoietic cell transplantation (AHCT) is the sole curative treatment. AHCT is often referred to as 'bone-marrow transplantation'. AHCT involves transplanting blood cells from a healthy donor to a patient. It is now known that the curative effects of AHCT results from the capacity of immune system cells (immunotherapy) to recognize and target tumor cell-surface proteins called minor histocompatibility antigens (MiHAs). MiHAs function as ‘signals’ for immune system cells. Although approximately 200,000 subjects diagnosed with HC have been cured with AHCT, the use of adoptive immunotherapy is hampered by two factors: i) the variable anti-HC activity of AHCT, and ii) the risk of a devastating complication, graft-vs.-host disease (GVHD) whereby donor cells present in the graft attack the patient (host) tissues.
Currently, the unpredictability of these two factors seriously limits the success rate of adoptive immunotherapy. As a result, AHCT, a potentially curative treatment, is used to treat only 20% of patients with refractory HCs. PCITP aims at developing a genetic test allowing clinicians to select the best donor thus reducing the incidence of GVHD and consequently increasing the frequency and safety of AHCT. Decreased incidence of GVHD will reduce mortality, morbidity and associated costs of treating patients with HCs. Identifying the best “donor-host” match with the genetic test being developed at PCITP will increase the use of AHCT and make this powerful therapy available to a greater number of HCs patients.
PCITP is also devising new clinical protocols to enhance anti-HC activity by targeting immune cells to specific MiHAs. Adoption of MiHA-targeted immunotherapy will allow for the safe and more effective targeted treatment of patients with otherwise fatal HCs without increasing the global cost of HC treatment.
Deliverables from the project’s main activities will allow: i) to select the best AHCT donor for a given patient with HC and ii) to tailor AHCT components as a function of the donor/recipient genotype and the proteome of the cancer cells. Full realization of these goals depends on the successful implementation of the genetic test in clinical settings as well as a broad adoption of MiHAs-targeted immune cells by clinicians.