"text-align: center;">Engineered Tumor-Infiltrating Lymphocytes- New Approach to Ovarian Cancer
Ovarian cancer is the most lethal gynecologic cancer. Less than one-half of patients survive for more than five years after diagnosis. Ovarian cancer affects women of all ages but is most commonly diagnosed after menopause. More than 75% of affected women are diagnosed at an advanced stage because early-stage disease is usually asymptomatic and symptoms of late-stage disease are nonspecific.
Immunogenic tumors can benefit from different immunotherapeutic interventions. Among them, adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TILs) is effective in mediating tumor regression, especially in melanoma, where about half of patients can achieve an objective response and one-fourth of them can expect complete and durable tumor rejection.
Recent technological advances have accelerated the identification of T-cell specificities against so-called tumor neo-antigens, resulting from non-synonymous somatic tumor mutations, and have shown their successful implication in immune-mediated rejection of melanoma, lung cancer, leukemia, and gastrointestinal cancers. Several studies have also indicated that tumor neo-epitope recognition underlies clinical response in patients receiving immune checkpoint blockade therapy or ACT of autologous TILs.
Epithelial ovarian cancer (EOC) is a tumor with not only purportedly relatively low mutational load, but also susceptible to immune recognition. Spontaneous anti-tumor responses, both as tumor-specific lymphocytes and antibodies, were identified in about half of the patients with advanced EOC, and cytotoxic T cells have been isolated from patients’ tumor, ascites, or peripheral blood. Of note, the presence of CD8+ TILs has been linked to better prognosis in late-stage EOC patients. Immunotherapy could thus be promising in EOC.
In this direction, scientists at the Ludwig Institute have now showed that ovarian tumors harbor highly reactive killer T cells and demonstrated how they can be identified and selectively grown for use in personalized, cell-based immunotherapies.
“Tumors whose cells tend to be highly mutated, like those of melanoma and lung cancer, are the ones that respond best to immunotherapies,” said Ludwig Lausanne investigator Alexandre Harari. “It has long been a question whether we’d even be able to detect sufficiently mutation-reactive T cells in patients with tumors that have low mutational loads.”
Like stated earlier, cancer cells that have a relatively large number of mutations in their DNA, and T cells that recognize mutations on cancer cells tend to decline significantly when the cells are expanded in culture. In order to circumvent these problems, the team developed a new methodology to identify highly reactive TILs and expand them in a manner that, rather than diluting the juiciest TILs, enriches them instead; this allowed them to compare the activity of TILs that target neoepitopes with their counterparts in the peripheral bloodstream.
The researchers show that killer T cells isolated from ovarian tumors using their method are much better at both recognizing neoepitopes than are those isolated from blood.
“We could even compare T cells from the two compartments targeting the exact same mutation and show that the TILs were more functional than the T cells we collected from the peripheral bloodstream,” says Harari.
Notably, the researchers found that, using their methods, highly reactive TILs could be obtained from some 90% of the ovarian cancer patients whose tumor samples they examined.
“The big message,” says study co-author, George Coukos, director of the Ludwig Institute for Cancer Research “is that future cell-based therapies can be envisioned for low mutational load tumors and should prioritize the use of TILs over T cells collected from peripheral blood. This novel strategy to obtain enriched TILs also offers great therapeutic opportunities.”
