http://astrocytomaoptions.com/immunotherapy/
PD-1 ANTIBODIES (NIVOLUMAB AND PEMBROLIZUMAB)
Late in 2014, the FDA approved two novel drugs for metastatic melanoma. These two drugs, pembrolizumab (Keytruda) and nivolumab (Opdivo) are both antibodies against PD-1, an immune checkpoint found on the surface of immune cells, that leads to anergy (deactivation) or death of immune effector cells when in contact with PD-L1 (ligand for PD-1) expressed on other cells. Though the PD-1/PD-L1 immune checkpoint system evolved as an important means to prevent autoimmunity conditions, the system is clearly co-opted by tumors to escape targeting by host immune cells. As of this writing in July 2016, there are no less than 13 trials currently recruiting glioblastoma patients for therapy involving nivolumab or pembrolizumab, and one trial testing a novel PD-L1 antibody (MEDI4736). The first trial for high grade gliomas to combine a dendritic cell vaccine with a PD-1 antibody is the AVERT trial at Duke University, which opened in early 2016 (NCT02529072). A second trial called CAPTIVE, opened in June 2016, combines the DNX-2401 adenovirus with pembrolizumab (NCT02798406). These two trials are likely the leading edge of the future of immunotherapy: combination of vaccine or oncolytic virotherapy with immune checkpoint blockade.
Preclinical evidence supporting this combination in high grade glioma comes in the form of a study published online in July 2016, by a team of UCLA researchers [1]. In this study, mice were treated with subcutaneous injections of a lysate-pulsed dendritic cell vaccine prepared from murine progenitor bone marrow cells and GL261 mouse glioma cell lysate. Mice were treated with vaccines at either the first day of intracranial GL261 glioma implantation, or at day 3 after tumors were established. Dendritic cell (DC) vaccination significantly increased survival times only in the group receiving early vaccination. In contrast, no prolongation of survival was seen in mice receiving later vaccination, in spite of tumor infiltration by glioma-reactive CD3+ lymphocytes in these mice.
PD-1 was increased on tumor-infiltrating lymphocytes in both untreated and DC vaccinated mice compared to splenic lymphocytes, indicating a localized immunosuppression in the tumor environment. Following DC vaccination, PD-1 was the only marker of immune inhibition increased in the tumor-infiltrating lymphocyte population. All other markers examined, including CTLA-4 (target of the drug ipilimumab) and TGF-beta, were downregulated following vaccination.
These observations led the researchers to treat mice with established gliomas with the combination of DC vaccination plus PD-1 monoclonal antibody (similar in function to the FDA-approved antibodies nivolumab and pembrolizumab). Remarkably, while no survival benefit was observed in mice treated with either vaccine or PD-1 antibody alone, 40% of mice treated with the combination survived at least to day 60 (none of the mice in the other arms survived to day 40).
The survival benefit of the combined therapy was found to be completely dependent on CD8+ cytotoxic T-lymphocytes, as depletion of these cells in the mice wiped out any benefit of treatment. Though mice in both DC vaccine treated, and DC vaccine plus PD-1 antibody treated groups had increased infiltration of CD8+ lymphocytes into their tumors, only combination treated mice had increased proportions of activated CD8+ CD25+ T-cells, showing that PD-1 antibody in addition to DC vaccine was necessary to maintain an activated population of CD8+ T-cells in the tumor environment.
Combination treatment also increased populations of tumor-infiltrating memory T-cells, and when surviving mice from the combination treatment group were re-challenged with a second injection of GL261 glioma cells in the contralateral brain hemisphere at day 60, they again survived significantly longer than untreated controls, though they had no additional treatments beyond the initial treatment at the time of the first tumor cell injections.
GBM samples taken from clinical trial patients before and after treatment with DC vaccines at UCLA showed both abundant expression of PD-L1 (the ligand for PD-1) in the tumor environment, as well as increased PD-1 expression on CD8+ tumor-infiltrating lymphocytes following dendritic cell vaccination. This demonstrates that, as seen in mice, PD-1 expression is a mechanism of immunosuppression following DC vaccination in human patients, a means of tumor resistance to the treatment.
Ex vivo, tumor-infiltrating lymphocytes taken from GBM patients undergoing resection showed greatly increased cytotoxicity against tumor cells when PD-1 antibody was added to the co-culture.
Significance: this study clearly shows that tumor lysate-pulsed dendritic cell vaccination is not sufficient to increase survival in mice with established gliomas, and that additional reversal of local immunosuppression with PD-1 antibody is also required. Human GBM tissue showed the same increase in PD-1 expression following dendritic cell vaccination, as a means of tumor resistance to treatment. Pending demonstration of the safety of combining dendritic cell vaccinations with PD-1 antibodies in current trials for high grade glioma, future vaccine trials should logically include such antibodies (eg. nivolumab or pembrolizumab), especially for patients with significant residual tumor post-resection. This combination treatment is likely necessary to bring the benefits of anti-tumor vaccines to a patient population that otherwise might not significantly benefit – those with significant residual tumor burden.
- PD-1 blockade enhances the vaccination-induced immune response in glioma. Antonios et al. 2016.
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Thank you Stephen for aways giving us hope.
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