Triggering an Immune Response in Ovarian Cancer

Trial Shows Personalised Medicine Benefit In Cancer Patients
by Mark L. Fuerst

A novel personalized vaccine made from an ovarian cancer patient’s tumor tissue and immune cells was found in early research to stimulate potent therapeutic immune responses, extending overall survival for patients with recurrent disease.

The vaccine, made from a processed sample of the tumor and delivered via a patient’s own immune cells, was well tolerated and safely administered and can be made in sufficient quantities with relative ease, the researchers said. The immune responses elicited were “vigorous” and targeted both known cancer antigens as well as a broad variety of neoantigens expressed by cancer cells.

“This study clearly proved that whole-tumor vaccination effectively mobilizes antitumor T-cell immunity in ovarian cancer. The vaccination itself amplified T-cell responses against mutated neoantigens derived from individual somatic tumor mutations, and this included stimulating the T cells against previously unrecognized neoantigens, as well as novel T-cell clones of markedly higher activity against previously recognized neoantigens,” the study’s lead author, Janos Tanyi, MD, of the Perelman School of Medicine at the University of Pennsylvania, told MedPage Today.

He explained that although ovarian tumor cells are known to express neoantigens, the malignancy has so far proved largely resistant to immunotherapies, including traditional cancer vaccines that stimulate an attack by killer T cells. Ovarian tumors also harbor T regulatory cells, whose job it is to suppress killer T cells.

“The key finding was that an individualized dendritic cell vaccine was able to initiate T-cell response against neoantigens, which otherwise was completely unrecognized by the immune system before vaccination.”

Earlier research by the team showed that production of oxidized lysate-pulsed dendritic cells and intranodal injection of a vaccine was feasible in ovarian cancer, and the new study builds on that data. The investigators made personalized vaccines by sifting through a patient’s peripheral blood mononuclear cells for suitable precursor cells. The cells were grown in the laboratory into a large population of dendritic cells, which are essential for an effective T-cell immune response. The dendritic cells were exposed to prepared extracts of the patient’s tumor, activated with interferon gamma, and then injected into the patient’s lymph nodes in order to prime a T-cell response.

The oxidized autologous whole-tumor cell lysate was given alone to five patients, in combination with bevacizumab to 10 patients, and with bevacizumab plus low-dose intravenous cyclophosphamide in 10 patients, until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events, the researchers reported.

Vaccination induced T-cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. At 1 year, all of the patients who received the whole-tumor lysate plus the two drugs were alive, compared with 60% of patients who received just bevacizumab and cyclophosphamide without the vaccine. Vaccination also amplified T cell responses against mutated neo-epitopes.

The whole-tumor lysate contains all the neo-epitope peptides characteristic for the actual patient, Tanyi explained. “This could lead to a cost-effective way of producing an individualized cancer vaccine. The individual patient’s tumors are not needed to be sequenced in order to identify and create these neo-epitope peptides, which otherwise is a very expensive procedure. Instead, neo-epitopes in the lysate from the actual patient can be used to generate an immune response because they are already in the whole tumor lysate.”

The personalized vaccine produces immune responses against neoantigens, which is important in ovarian cancer because each patient’s cancer is different and changes even further during disease progression, he said. “Targeting these neoantigens can cover most of the tumor cells in the patient, as this vaccine targets thousands or even more neoantigens.”

Tanyi noted that the study used two potentially synergistic immunomodulatory drugs that are commonly used in advanced recurrent ovarian cancer patients as adjuvants to increase the effectiveness of the vaccine: Cyclophosphamide is known to decrease the CD25 regulatory T-cell activity, which “otherwise would shoot down the generated immune response, and bevacizumab as an anti-angiogenic agent decreases the endothelial barrier and makes it more penetrable for CD8-positive cytotoxic T lymphocytes.”

In the future, additional combinations with checkpoint inhibitors will further increase the T cell responses, he said, noting that the team had previously shown that the combination of a whole-tumor antigen vaccine markedly increased the efficacy of checkpoint blockade immunotherapy.

The next step is to test this personalized vaccine concept earlier in the disease process as a maintenance treatment in patients who have just finished first-line therapy. “Many of these patients reach ‘no evidence of disease’ [status] just when completing first-line therapy. Unfortunately, most of them recur. We propose that if dendritic cell vaccine immunotherapy can be started much earlier, during or immediately after the first-line treatment, it might decrease the recurrence rate or increase the disease-free interval of this devastating disease.

“Individualized immunotherapy is the future, as each patient’s disease has unique features and nonsynonymous mutations that can be targeted,” Tanyi continued. “We need to help the immune system to overcome immune resistance and define these neoantigens as foreign and initiate an antitumor immune attack. This whole tumor lysate-induced dendritic cell vaccine proved to be an effective method to alert the immune system against these neoantigens.”

This article was published by MedPage Today.

Leave a Reply

Your email address will not be published. Required fields are marked *

This blog is kept spam free by WP-SpamFree.

Back to Home