Adoptive cell transfer immunotherapy is one of the most promising new treatments for people with hard-to-treat cancers. However, the process is complex and needs fine-tuning in order to develop more treatment strategies that will work for more people.
In a new study looking at adoptive cell transfer products bearing a transgenic T-cell receptor (TCR), researchers at the UCLA Jonsson Comprehensive Cancer Center have identified a discordant phenomenon in which a subset of patients displayed profoundly decreased expression of the transgenic TCR over time, despite the transgenic TCR being present at the DNA level. This gave rise to the observation that structural changes to the DNA via DNA methylation make it inaccessible for transcription and translation, which is an influential step in the flow of genetic information from DNA to RNA. This can be one clue into why some patients stop responding to this type of immunotherapy.
"The issue is this phenomenon happens over time," said lead author Theodore Scott Nowicki, MD, PhD, clinical instructor of pediatrics and hematology/oncology at the David Geffen School of Medicine at UCLA. "We're hoping this can help inform the design of future generations of these types of therapies and pinpoint different vectors that might be more or less vulnerable to this phenomenon."
The study was published online in Cancer Discovery, a journal of the American Association for Cancer Research.
Adoptive cell transfer immunotherapy works by taking a patient's own T cells, which are one of the components of the immune system, and genetically modifying them in the laboratory to target tumor-specific antigens on the surface of the tumor. The new army of tumor-specific T cells are then reinfused back into the patient to help attack the cancer.
A key component of adoptive cell transfer therapy requires genetically modifying T cells to target cancer cells. This is often done with viral transduction agents with either lentivirus- or retrovirus-based products to express either a cancer antigen-specific TCR or chimeric antigen receptor (CAR).
In order to develop more efficient cell therapies, Nowicki and colleagues are studying the genetic mutations of T cells to understand the structural changes to DNA over time. This could reveal why adoptive cell transfer therapy is more likely to work in some patients versus others and help inform the future design of next-generations of the therapy.
The team analyzed 16 clinical transgenic adoptive cell therapy samples collected before and during treatment from patients with melanoma and sarcoma. This allowed the team to look at the expression of the transgenic TCR at the DNA and protein level. It gave them insight into what proportion of the cells displayed impaired expression of the transgenic TCR. They were then able to assess the degree of DNA methylation present in the retroviral vector's promoter region over time, and correlate this degree of DNA methylation with repression of the transgenic TCR.
The study can help researchers in the design of future generations of cellular immunotherapies to help treat people with advanced cancers.
The study's lead and senior author is Dr. Nowicki. The study was conducted under the mentorship of Dr. Antoni Ribas, professor of medicine and director of the tumor immunology program at the UCLA Jonsson Comprehensive Cancer Center. Both Dr. Nowicki and Dr. Ribas are members of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research. Other authors include Colin Farrell, Marco Morselli, Liudmilla Rubbi, Katie Campbell, Mignonette Macabali, Beata Berent-Maoz, Begona Comin-Anduix and Matteo Pellegrini, all of UCLA.
The research was funded in part by grants from the National Institutes of Health, the Tower Cancer Research Foundation, the Hyundai Hope on Wheels foundation, the Parker Institute for Cancer Immunotherapy and the Ressler Family Fund.
Nowicki, T.S., et al. (2020) Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy. Cancer Discovery. doi.org/10.1158/2159-8290.CD-20-0300.