The most significant advance in the treatment of cancer patients over the last few decades has been the discovery of innovative ways to improve the ability of the body’s immune system to recognize and kill cancer cells. Cancer cells have multiple ways to shield themselves from the immune system, but innovative new drugs have been developed that work by removing some of these shields, making immunotherapy, not only possible, but in some cases, remarkably effective. These drugs have revolutionized cancer treatment, and are used to treat a very broad spectrum of cancer types.
One of the immunotherapy methods consists of antibodies that can either latch onto killer T cell receptors on the one hand, or certain molecules expressed by tumour cells to which the T cell receptors recognize and bind. T cells are a type of white blood cell that help the immune system to maintain health and protect from disease and infection. T-cell receptors are proteins on the surface of T-cells that recognize foreign substances and activate the T cells to bind to them.
Immunotherapy can activate the immune system to far more efficiently kill cancer cells and cause enduring tumour remissions, at least in some patients. However, one of the problems that can be encountered with this strategy is that the killer T cells frequently have problems infiltrating into the dense, ‘stiff’ tissue that often comprises solid tumours. There are a number of reasons for this and one is that non-cellular components of tumour tissue which comprise what is called the extracellular matrix (ECM) can organize in such a way to impede T cell invasion into the tumour tissue. Two of these mechanical molecular “scaffolds” – fibronectin and collagen – contribute to dense mechanical scaffold structures.
Working with a new experimental antibody drug developed by Genentech, the laboratory of Dr. Robert Kerbel in Biological Sciences assessed the ability of the new drug to improve cancer therapy outcomes in pre-clinical models using a highly successful type of immunotherapy called PD-L1 antibodies. The new drug is a “disruptor” agent targeting an “organizer” molecule involved in building the structures of the tumour ECM. By combining the two antibodies, it was shown that remodelling of the abnormal ECM of tumours can take place in such a way that the level of killer T cell infiltration could indeed be enhanced, thus improving the anti-tumour impact of the immunotherapy.
The work in Dr. Kerbel‘s lab was led by Dr. Kabir Khan, a former CIHR Banting postdoctoral fellow and research associate, who worked closely with a team of Genentech colleagues over a four-year period, led by Dr. Weilan Ye. “Our pre-clinical work shows that these ECM structures are an obstacle to immunotherapy’s reach and benefits. We found that when you inhibit the organizer molecule, it results in having less of the dense scaffolds present, and therefore, allows more T cells or immune cells to move in to the tumour,” explains Dr. Khan, joint first author of the study. “Once the immune cells are in, they are also more functional and better able to fight the cancer cells; this is also a key aspect.” The studies involved a type of aggressive breast cancer called “triple negative”.
The next step in this research is to target the ECM organizer molecule and inhibit these dense molecular structures from building, potentially in clinical trials of patients with diagnosed triple-negative breast cancer who are receiving chemotherapy and already approved for immunotherapy, by adding on a “disruptor” antibody treatment.
The results of Khan et al. were published in the September 16, 2025 issue of Cell Reports Medicine. Another study and paper from Dr. Kerbel’s lab, and also led by Dr. Kabir Khan, that is designed to improve researchers’ ability to improve the accuracy of immunotherapy experimental studies, was published on March 16, 2025 in Cancer Research.