Dr. William V. Williams of BriaCell Therapeutics discusses overcoming solid tumor resistance, leveraging HLA matching and executing pivotal Phase III cell therapy trials.
Cell therapies have opened new treatment options for certain blood cancers, but solid tumors pose different challenges. Cancer cells can vary within the same tumor, while surrounding cells can interfere with the immune system’s ability to attack them. Researchers are also exploring how an off-the-shelf cell therapy could be personalized for individual patients without manufacturing a new treatment from scratch each time.
In an exclusive Xtalks Clinical Edge interview, Dr. William V. Williams, MD, FACP, President and CEO of BriaCell Therapeutics, discussed the biology behind solid tumor resistance, how human leukocyte antigen (HLA) matching could help personalize off-the-shelf therapies and the clinical trial and manufacturing decisions involved in bringing these treatments through development.
President and CEO
BriaCell Therapeutics
Why Solid Tumors Can Shut Down an Immune Attack
A solid tumor contains a mix of cancer cells that can become progressively different as they divide and accumulate mutations. Other cells within the tumor, including fibroblasts and macrophages, can also contribute to an environment that suppresses immune activity.
Researchers sometimes find immune cells inside a tumor that are already attempting to fight the cancer.
“You do a biopsy and you see the immune cells in there trying to attack the cancer, but the tumor microenvironment shuts them down,” said Dr. Williams.
Immune checkpoint inhibitors can help reactivate these suppressed immune cells. However, their effectiveness often depends on whether the patient already has an immune response against the cancer. Some tumors, including many breast cancers, have limited pre-existing immune activity.
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“So what you need is a way to induce that immune response, and then the combination with the checkpoint inhibitor can potentially be very effective in that case,” he explained as a potential strategy for these cases.
This is one of the ideas being explored in cell-based immunotherapies for solid tumors.
“The way that these antigens are recognized is that they bind to HLA molecules much like a hot dog fitting into a hotdog bun.”
– Dr. William V. Williams
Off-the-Shelf Cell Therapy: How HLA Matching Fits In
Traditional personalized cell therapies typically come from a patient’s own cells, which are collected, processed in a laboratory and returned for treatment. This can involve considerable time, expense and specialized manufacturing.
An off-the-shelf cell therapy can be manufactured in advance, with suitable cells selected for patients when treatment is needed.
“You’ve already pre-manufactured your cell therapy, and you can send the matching cells to the clinic to treat the patient,” noted Dr. Williams.
Researchers are exploring this approach through HLA matching. HLA molecules help the immune system recognize antigens, which are small pieces of proteins displayed to T cells.
As he explained it, “The way that these antigens are recognized is that they bind to HLA molecules much like a hot dog fitting into a hotdog bun.”
The combined antigen and HLA molecule is then presented to a T cell, which can recognize it and initiate an immune response.
Because some people share HLA types, developers can investigate whether pre-manufactured cell therapies selected according to a patient’s HLA profile can stimulate immune cells that also recognize their cancer.
“What does the data show and does it make sense? And when the two come together, then that helps you decide to go with a particular biomarker.”
– Dr. William V. Williams
BriaCell is pursuing this strategy through its investigational Bria-OTS and Bria-OTS+ platforms. Its lead candidate, Bria-IMT, is also an investigational off-the-shelf therapy, although it is currently being studied without HLA-based patient selection.
Finding Clues to Which Patients May Respond
Even when a therapy is selected using HLA matching, researchers still need to understand why some patients respond better than others.
BriaCell’s lead cell line expresses dozens of breast cancer-associated antigens and can also activate natural killer cells, which are part of the body’s innate immune system. These features are being investigated to see how they may influence treatment responses in different patients and cancer types.
Tumor grade describes how abnormal cancer cells appear under a microscope. “One of the things that we noted early on is that patients with grade one or grade two breast cancer had the best responses. Well, our cell line is derived from a grade two breast cancer tumor, so that kind of made sense,” said Dr. Williams.
The observation was biologically interesting, although further evidence would be needed before tumor grade could be used as a reliable patient-selection biomarker.
For smaller biotechnology companies, generating enough data to establish statistical confidence in every possible biomarker can be difficult. Dr. Williams emphasized that researchers must consider both the clinical observations and whether those findings are consistent with the therapy’s proposed mechanism.
“What does the data show and does it make sense? And when the two come together, then that helps you decide to go with a particular biomarker,” he noted.
BriaCell is continuing to investigate HLA matching and other potential markers, including tumor-associated antigens, circulating tumor cells and circulating DNA and RNA, to understand which patients may benefit from its therapies.
“We have to just continue to treat patients who we think are going to benefit the most, and then continue to look at the biomarker data as we go along so that we can continue to hold our patient selection criteria to those who will benefit the most.”
– Dr. William V. Williams
The Decisions Behind a Pivotal Cell Therapy Trial
BriaCell’s Phase III Bria-ABC study is evaluating Bria-IMT in combination with an immune checkpoint inhibitor in patients with advanced metastatic breast cancer. Designing the trial involved decisions about how to demonstrate clinical benefit while accounting for the company’s resources and the treatment options available to patients.
“So the basic issue whenever you design a pivotal study is how can you do the study that’s going to convince the FDA, the regulatory agencies, to approve your therapy at the same time while not breaking the bank, so to speak,” he said.
The study uses a randomized, open-label design in which participants receive the investigational treatment regimen or a treatment selected by their physician.
The physician’s-choice approach allows for different established treatment options, depending on the patient’s condition and previous therapies. “So it’s basically what the patient would’ve been treated with anyway if they were not in the study,” he explained.
BriaCell’s manufacturing process has progressed from producing doses in a research laboratory to larger-scale production under good manufacturing practice (GMP) standards. The company is also working with FUJIFILM Biotechnologies California to expand manufacturing capacity, while tightening quality controls and product-release criteria and qualifying and validating analytical tests.
As BriaCell continues its clinical studies, it is also investigating how patient-selection biomarkers could help guide future treatment decisions.
“We have to just continue to treat patients who we think are going to benefit the most, and then continue to look at the biomarker data as we go along so that we can continue to hold our patient selection criteria to those who will benefit the most,” said Dr. Williams.
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