Blood cancer research extended further with LLSC partnerships

People with triple refractory myeloma (where the disease is not responsive to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies) unfortunately have a poor prognosis. While chimeric antigen receptor T-cell (CAR-T) therapies show great promise in treating the disease, the cost and complexity of CAR-T manufacturing has limited its accessibility, particularly in Canada. Bispecific antibodies, however, can provide a treatment option that is more broadly accessible with shorter patient wait times, increased dosing flexibility, and at a lower cost than CAR-T therapies. Although a bispecific T-cell engager (BiTE; teclistamab) was approved by Health Canada in 2023 for the treatment of myeloma, clinical access in Canada is still limited. Like BiTEs, bispecific natural killer cell engagers (BiKEs) may have less toxicity than T-cell targeting bispecific antibodies, though they are less explored and have fewer molecules in development.

Dr. Scott McComband and his research team have well-established expertise in myeloma target identification, identification of novel antibodies, and immunotherapeutic development. In this study, they propose to generate novel high quality ‘llama-derived single-domain antibodies’ (known as nanobodies) that bind strongly to proteins expressed on myeloma cells. The team will then use these new nanobodies to generate new BiTE and BiKE molecules to assess their functionality for inducing T-cell or NK-cell mediated myeloma killing. Downstream of this work, the team intends to rapidly translate one or more of the new therapeutics for clinical trials in Canada.

Survival rates for people with myeloma have significantly improved and more people are living longer with a better quality of life than before. While this is extremely encouraging, most individuals do relapse because of drug resistance. Two urgent challenges immediately become evident; the need to: identify novel therapeutic alternatives; and understand the mechanisms of treatment resistance to prevent or overcome myeloma relapses.

Dr. Keith Stewart and team endeavoured to detect unrecognized, vulnerable myeloma targets to establish a new approach to treating myeloma. PIKfyve was identified as a druggable novel target.

Among other molecules, the highly potent PIKfyve inhibitor PIK-001 has shown robust anti-myeloma activity in preliminary analyses. In this study, the researchers are further investigating the cytotoxicity, (i.e., the degree a substance can cause damage to a cell) of PIK-001 against human myeloma cells, exploring combination protocols with known myeloma therapeutics, and characterizing the mechanisms of resistance to PIKfyve inhibition.

The pre-clinical data obtained by this study will inform a planned phase 1 clinical trial design and further develop these novel potent PIKfyve inhibitors for regulatory approvals for clinical use. This will represent an important and exciting addition to the myeloma treatment arsenal for the myeloma patient community.

Acute myeloid leukemia (AML) is a genetically and biologically diverse group of diseases that is difficult to treat and has poor prognosis. In pediatric AML, the lack of patient samples and the limited number of leukemic cells in pediatric samples pose challenges for finding new targets for therapy.

To overcome these issues, this team has collaborated with other researchers to acquire many AML samples, so that a detailed analysis of these cells can be performed to identify potential molecules with anti-AML activity. The promising results of this study have highlighted several compounds of interest, and the identification of their potential targets and mechanisms of action may lead to development of new therapies for AML.

CAR T-cell therapy uses a patient’s own immune T cells to detect and kill cancer cells. The complex process involves extracting T cells from the blood and genetically modifying them in a lab to find and kill cancer cells. These supercharged cells are then put back into a patient’s bloodstream where they multiply and find and destroy cancer cells.

Until now, Canada has been without the laboratory facilities to modify these all-important T cells. BioCanRx’s Canadian-led Immunotherapies in Cancer (CLIC-01) trial is unique because it is the first ever to develop and manufacture CAR T cells in Canada. With more than 70 patients on the trial, CLIC has demonstrated that patients can be treated with Canadian-made CAR-T cells in a timely fashion, with the possibility of durable responses.

The trial is now working to add in more clinical and manufacturing sites to build a larger national footprint for access and implementation of this CAR-T cell trial, with the goal of eventually reaching market authorization in Canada. Dr. Kekre has been leading the CLIC-01 trial, which treats patients with relapsed/refractory blood cancers. In this expansion phase of the trial, Dr. Kekre hopes to grow the research program so that more Canadians all over the country can access this innovative, life-saving therapy.