Imagine this scenario: A woman with advanced pancreatic cancer who researched potential new treatments discovered a novel approach called TCR gene therapy that targets the KRAS G12D mutation.
The patient had undergone every standard of care treatment, including surgery, radiation, and multiple rounds of chemotherapy. But malignant lung lesions continued to grow. And although continued chemotherapy was a potential option, she wanted something more. She did some research and found a published report describing a patient with metastatic colorectal cancer who was successfully treated with this type of adoptive cell therapy, a kind of immunotherapy.
The patient contacted the researcher, Eric Tran, Ph.D., who is now with the Earle A. Chiles Research Institute (Portland, Oregon), a division of Providence Cancer Institute of Oregon. All appropriate approvals were granted, and the patient received the treatment. Today, she has a 72 percent reduction in the size of her tumors.
Although the treatment is novel, it’s important to read beyond the headlines, explains one of the world’s leading cancer immunotherapy experts, Elizabeth Jaffee, M.D., the Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Baltimore, Maryland), Co-Director of the Skip Viragh Center for Pancreatic Cancer, and Associate Director of the Bloomberg–Kimmel Institute for Cancer Immunotherapy.
“We always want to give people hope, and there is real hope because there are many pancreatic cancer clinical trials underway that can potentially help many people,” says Jaffee. “It’s very clear that we need much better treatments for advanced disease. But this case report is very early work, the study was very small, and there are many unanswered questions about the mechanisms behind this response. Hopefully those questions will be answered with more research, and then we can gauge what it can add to the knowledge of pancreatic cancer immunotherapy approaches.”
Plus, Jaffee adds, the approach is currently not applicable to many patients, since it is dependent on a specific HLA (human leukocyte antigen) genotype. The other caveat is that the report mentions another patient who underwent the treatment and died. The reason is still unclear. As is the explanation for why it worked so well in the other patient, though Jaffee suspects it may be related to the fact the cancer had spread to her lungs, not liver. “Although we don’t know why, immunotherapies don’t seem to work well on liver metastases,” says Jaffee. “Unfortunately, the majority of patients, like the patient who did not respond to this therapy, have liver metastases.”
What Is TCR Therapy?
TCR therapy is a type of cellular immunotherapy. With immunotherapy, immune cells known as T cells have certain proteins—receptors—that are able to recognize and bind to antigens that are mostly foreign, like bacteria. This occurs when those invading antigens are presented by other immune system cells called antigen-presenting cells (APCs). Upon binding, the T cell is then activated to destroy cells harboring this antigen.
Although all cancer cells have antigens, T cells only activate to destroy cancer cells when their receptor specifically recognizes the combination of the antigen and the presenting molecule on the surface of the antigen- presenting cell. T cells must match the presenting molecules of the antigen-presenting cells—this forms the basis for the “matching” that is required. “Immunotherapy really isn’t a one-size-fits-all approach,” says Jaffee, who is also chair of President Joe Biden’s Cancer Panel. “It’s personalized to meet the precise needs of each patient.”
One type of cancer immunotherapy is chimeric antigen receptor (CAR) T cell therapy, which is approved by the U.S. Food and Drug Administration for treating certain types of blood cancer, such as leukemia and lymphoma. But it doesn’t work well on solid tumors.
That’s just one reason why scientists are researching another approach called T cell receptor (TCR) therapy. Like CAR T cell therapy, TCR therapy involves the modification of T cells in a lab. However, unlike CAR T cell therapy, it doesn’t rely on human-made receptors that can only target things on the surface of cells. Rather, it capitalizes on the natural mechanisms of T cells.
Some research shows that TCR therapy is unique because it recognizes many types of cancer that have overexpression of a specific antigen within the cell, if it is presented a specific human leukocyte antigen (HLA), which can be found on the surface of tumor cells in the same manner as an antigen-presenting cell.
In this study, Tran genetically engineered the patient’s T cells so they could spot a mutant protein hidden inside her tumor cells while leaving healthy cells alone. This process is very complex. The clinical trial designed for the patient featured in the study was built on the findings of the 2016 New England Journal of Medicine article that Tran authored while at the National Institutes of Health. In that study, Tran found tumor-infiltrating T cells that targeted a common cancer mutation in a patient with metastatic colorectal cancer. These mutation-reactive T cells were expanded in the lab and then over 100 billion of the T cells were infused into the patient, which led to regression of her metastatic disease.
An overall objective partial response of 62% was achieved in the regression of metastatic lung lesions at one-month follow-up, and an overall partial response of 72% in tumor regression was achieved by the six-month mark. Additionally, the engineered cells made up 2.4% of all circulating T cells at six months post treatment.
Because the pancreatic cancer patient’s tumor contained the same mutation as the patient described in the 2016 study, as well as the right HLA match, Tran’s team was able to use the mutation-reactive T cell therapy for her.
It is not clear why the experiment did not work in the other patient.
Larger Clinical Trial Underway
Based on this work, a larger clinical trial is underway that will include 24 patients. The trial is dubbed Hotspot TCR-T: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T).
Eligibility includes those patients with metastatic or locoregionally advanced epithelial cancers that are considered incurable. These include certain cancers of the breast, gastrointestinal tract (colon, stomach, gallbladder, bile ducts, pancreas, and liver), lung, prostate, and bladder. Patients with melanoma or cancers of the blood, soft tissue, or neurological tissue are not eligible.
“I think one of the real messages here is that we are making progress,” says Jaffee. “The technologies that we have available for molecular profiling are influencing treatment in some cases, and treatments are also improved. Ongoing research will make a difference for patients. It’s a matter of when, not if. I think all of us in the field really do believe that.”