Authors: Eric Tran, Ph.D., leader, Adoptive Cell Therapy Laboratory, Providence Cancer Institute of Oregon
Rom Leidner, M.D., medical oncologist, co-medical director, Providence Head and Neck Cancer Program, Providence Cancer Institute of Oregon
In June 2021, our team conducted a single-patient clinical trial at Earle A. Chiles Research Institute, a division of Providence Cancer Institute of Oregon, that involved engineering a woman’s T cells to target a “hotspot” mutation expressed by her cancer, growing the number of T cells to 16 billion and then infusing them back into her body.
This approach is called “T-cell receptor (TCR) gene therapy” because the basis of it involves inserting a T-cell receptor gene into a patient’s T cells to reprogram them to target the cancer. These gene-engineered T cells are then multiplied in the lab to large numbers, typically billions, and then reinfused back to the patient.
TCR gene therapy is one type of adoptive cell therapy, also known as T-cell transfer therapy, and is still highly experimental. T cells are considered “living drugs” since they have the capacity to replicate, survive and persist in the patient after infusion.
Currently, the Earle A. Chiles Research Institute and the National Institutes of Health (NIH) are the only two academic facilities in the United States with investigator-initiated “homegrown” clinical trials targeting cancer mutations using TCR gene therapy.
Our study about the trial was published June 2, 2022, in The New England Journal of Medicine. It is the first report of metastatic pancreatic cancer regression through T-cell transfer therapy with mutation-targeting genetically engineered T cells.
Second generation research
The 2021 trial was the second iteration of a T-cell transfer therapy study.* In the first-generation approach, a tumor was removed from patients with metastatic gastrointestinal cancer, and the T cells within the tumors were expanded in the lab. The tumor-infiltrating T cells that specifically targeted the patients’ cancer mutations were identified, expanded and then reinfused back to the patients.
In two patients, one with bile duct cancer (Tran et al. Science 2014), and the other with colorectal cancer (Tran et al. NEJM 2016), the infusion of mutation-reactive T cells led to regression of metastatic disease, and both patients are alive and well to this date, about nine and seven years after therapy, respectively.
In the 2016 New England Journal of Medicine report of the patient with colorectal cancer, the therapeutic T cells were found to actually target a well-known mutation in a protein called KRAS, which is implicated in roughly 25% of all cancers.
Kathy Wilkes, the patient who participated in the 2021 trial, had pancreatic cancer that had metastasized in her lungs, but she shared something in common with the 2016 patient with colorectal cancer: the KRAS mutation and another genetic factor, called human leukocyte antigen (HLA). HLA is the immune system's way of distinguishing its own cells from foreign and harmful substances. In combination, a TCR that is HLA matched to a patient can “look inside" a cancer cell to see internal mutations, and then target and destroy the cancer cell.
Once the FDA granted approval to a single patient expanded access trial for Kathy (also known as "compassionate use"), the TCRs that targeted mutated KRAS from the patient with colorectal cancer were genetically isolated, and then inserted into the T cells derived from Kathy’s blood, thereby reprogramming them to attack the KRAS mutation expressed by her cancer.
Within six months of treatment, Kathy’s tumors had shrunk by 72%. At present, most of Kathy’s tumors remain decreased in size, and she is living as if she were cancer-free without needing other treatments.
New clinical trial is next step in the evolution
What we learned from the most recent study has helped shape a new phase I clinical trial. The new trial will evaluate whether TCR gene therapy targeting mutations, in combination with two additional immunotherapies, is safe and effective in 24 patients with locally advanced or metastatic epithelial cancers that are considered incurable. Epithelial cancers are responsible for 85% of annual cancer deaths and comprise most of the common solid tumor types.
The study, known as Hotspot TCR-T, will infuse engineered T cells in patients with certain gene mutations in their cancer, who have an HLA that matches a mutation-specific TCR.
Patients will undergo extensive immune monitoring to determine persistence, the rate at which T cells circulate in the patient’s blood or the tumor after therapy, and to understand why patients respond or don’t respond to the therapy. What we learn from these patients, we can apply in the next trial iteration, which already is in development.
Decades in the making
Since the FDA approval five years ago of the first gene-engineered T-cell therapy, adoptive cell therapy research has taken off and there is a lot of excitement in the field. But not many facilities – academic or industry – have the specialized infrastructure and expertise to both manufacture these gene-modified cell products and conduct the cutting-edge, immune monitoring intensive clinical trials to deliver these "living drugs" to patients.
Providence is in the unique position to do this work and evolve the research. Providence Cancer Institute has been building the requisite infrastructure since the 1990s to support this world-class work. Clean room facilities, biobanking next to the operating rooms, labs next to the oncology clinics, premiere clinical trials staff, an expert regulatory team and generous donors make it possible to continue research like this.
Learn more about specialized facilities at the Earle A. Chiles Research Institute and Dr. Tran’s Adoptive Cell Therapy Lab.
Read more about the latest trial here:
Hotspot TCR-T: A Phase I/Ib Study of Adoptively Transferred T-cell Receptor Gene-engineered T Cells (TCR-T) Targeting Tumor-Specific Neoantigens, with in Vivo CD40 Activation and PD-1 Blockade, for Patients with Incurable Cancers
*The 2021 trial was the second iteration of a T-cell transfer therapy study, which was led by Eric Tran, Ph.D., while he was training at the NIH with Steve Rosenberg M.D., Ph.D.
Dr. Tran also is assistant member, Earle A. Chiles Research Institute, a division of Providence Cancer Institute.
Dr. Leidner is associate member, Earle A. Chiles Research Institute, a division of Providence Cancer Institute.
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