“Compound A” Could Make Multiple Myeloma More Visible to Naturally Occurring T Cells, UH Seidman Research Suggests

Innovations in Cancer

Research underway at UH Seidman Cancer Center has identified a newly discovered compound that could enlist your body’s naturally occurring T cells to more effectively fight multiple myeloma – a cancer with inferior survival compared with age-matched populations suffering from other blood cancers.

James J. Driscoll, MD, PhD, Assistant Director of Hematologic Malignancy Research at UH Seidman, and colleagues focused on novel ways to promote and activate proteosomes in multiple myeloma.

“Proteasomes degrade intracellular proteins to generate antigenic peptides that are recognized by the adaptive immune system and promote anti-cancer immunity,” they wrote in the journal Cancer Research Communications. “However, tumors subvert the antigen presentation machinery to escape immunosurveillance. We hypothesized that proteasome activation could concomitantly increase antigen abundance and diversity in multiple myeloma cells.”

To test their hypothesis, the research team conducted a high throughput screen on 3,000 candidate compounds.

“Our major hit from that was an HDAC6 inhibitor, which was already in the FDA pipeline, but it wasn't very effective,” Dr. Driscoll says. “Based on our hit from the first screen, we used a chemical compound library of over 9,000 compounds and we identified eight. Our best one is what we call Compound A.”

Writing in the journal Molecular Cancer Therapeutics, Dr. Driscoll and team described a novel molecule.

“Compound A increases the catalytic activity of the immunoproteasome,” he says. “That's the big apparatus in tumor cells, and that's what generates antigens that are presented on the tumor cell surface. Antigens are then recognized by a person’s naturally occurring cytotoxic T cells to kill the tumor cells. Our drug increases activity of that apparatus and makes the tumor cells more antigenic.”

In fact, research showed that Compound A increased the presentation of individual MHC-I–bound peptides by more than 100-fold and unmasked tumor-specific neoantigens on myeloma cells, Dr. Driscoll says.

The team has also tested Compound A in multiple myeloma cell lines and in patient bone marrow-derived CD138+ cells, as well as in mice with myeloma xenografts.  

“Compound A increased the anti-myeloma activity of allogenic and autologous T cells,” the team reported. “It was well-tolerated in vivo and co-treatment with allogeneic T cells reduced the growth of myeloma xenotransplants in NOD/SCID gamma mice.”

Meanwhile, the research team has been working with colleagues from Case Western Reserve University to enhance Compound A and make it more effective. They’re also looking at the most efficient way to ultimately bring it to clinical use. That may be as a topical agent as opposed to a systemic one, Dr. Driscoll says.

“We’re not quite ready to go to trial yet, but we’re interested in looking at cutaneous lymphomas and cutaneous melanomas to see if it works there,” he says. “That could give us a more rapid translation to the clinic, by having a topical application of this agent to target tumor cells and make them more antigenic to the host immune system.”

Though much work still remains, Dr. Driscoll says he’s encouraged by the progress and how this project fits into one of the main thrusts of current cancer research.

“Certain tumors are what's known as being hot tumors, and certain tumors are cold,” he says. “If they're cold, that means that the T cells or the immune system don't recognize tumor cells. They're not antigenic. As cancer researchers, one of our jobs is trying to turn tumor cells from cold to hot. That's basically what we're doing. Compound A is turning cold tumors hot.”

Turning them “hot” allows a person’s naturally occurring T cells to do their job – potentially avoiding the costs and shortcomings of CAR T-cell therapy, Dr. Driscoll says. This, he says, could be a paradigm shift for the field.

“Taken together, our results demonstrate the paradigm shifting impact of immunoproteasome activators to diversify the antigenic landscape, expand the immunopeptidome, potentiate T-cell–directed therapy, and reveal actionable neoantigens for personalized T-cell immunotherapy,” he says.