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Survivin may be target for immunotherapies in several malignancies
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Survivin, an inhibitor of apoptosis protein, may be an attractive target for a variety of immunotherapeutic approaches for cancer, according to study results.
Survivin is highly expressed by many cancer types, such as breast, pancreatic and lung cancers, as well as glioma and some forms of leukemia, lymphoma and multiple myeloma.
Research efforts at Roswell Park Comprehensive Cancer Center suggest targeting the survivin protein through novel vaccine approaches may be more effective than standard therapy alone for certain patients with glioblastoma.
Robert Fenstermaker, MD, chair of the department of neurosurgery at Roswell Park, and colleagues previously showed in preclinical models that active specific vaccination with a long peptide survivin immunogen contributes to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival.
In a study published earlier this year in Clinical Cancer Research, Fenstermaker and colleagues demonstrated that survivin is present on the outer cell membrane of murine and human glioma cells. They also reported antibodies in both flank and intracranial tumor models in preclinical GL261 gliomas and B16 melanomas.
“In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the surviving immunogen have antitumor activity in vivo,” researchers wrote. “Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches.”
HemOnc Today spoke with Fenstermaker about how the research team arrived at this unique approach, as well as how to make a more solid transition between murine models and humans.
Q: How did you arrive at this discovery that survivin is on the surface of cancer cells ?
A: We have been studying the cancer-associated molecule survivin for some time and have focused on targeting it immunologically to develop new therapies. We have developed a cancer vaccine that stimulates three different arms of the immune system, but we had expected that only two of the three arms would be useful for this purpose. Because survivin was long thought to be contained only within the interior of a cancer cell, we expected that antibodies produced by our vaccine would have no effect on tumor cells because they cannot normally gain access to the interior of the cell where survivin was known to reside. In order to confirm this, we tested highly purified survivin antibodies produced in response to our survivin cancer vaccine in tumor model systems. To our very great surprise, we found that these antibodies actually did inhibit tumor growth in these models. We then looked more closely at where these antibodies were binding to survivin and found it on the outer surface of a wide range of different cancer cells, primarily within small islands called “rafts” that float within the outer layer of the cancer cell that is exposed to the outside world.
Q: In which malignancies do you expect this discovery to have the biggest impact ?
A: Our work has demonstrated that survivin is present on the outer surface of cancer cells in many different types of malignancies, including those found in the brain, lung, breast, cervix, skin, colon and prostate, and on lymphomas and leukemia cells, as well. Therefore, the potential impact for survivin-targeting in cancer is very substantial and rests more with the difference in survivin expression between tumor tissue and normal tissue rather than the tumor type itself.
Q: How can this information be used to develop new therapies?
A : Survivin is very commonly expressed by cancer cells but infrequently by normal cells among adults. The presence of survivin on the outer surface of cancer cells means that it is exposed to anticancer therapies that specifically employ antibodies as targeting agents. This can include survivin antibodies attached to cell-killing drugs or radioactive agents, as well as the very promising FDA-approved chimeric antigen receptor (CAR) T cells.
Q: What is the potential effect on patient outcomes?
A: Advances in immunotherapy have provided great opportunities for patients with cancers that were previously difficult to treat. The identification of new potential targets for such therapies is a key element to advancing cancer therapy. Developments in CAR T-cell therapy have provided impressive results for patients and offer very promising avenues for development in other cancers. To date, these advances have been in patients with a limited spectrum of advanced cancers, including those who have been refractory to standard therapy. So far, the number of cell-surface targets treatable with CAR T-cell therapy has been limited. Our results provide a new avenue for targeting in other cancers that are not currently treatable with established CAR T-cell types.
Q: Where will the research go next?
A: We are developing vaccine, antibody and CAR T-cell therapies for cancer that target cell-surface survivin. We expect that, as a result of the findings in this study, there will be a strengthening of interest in survivin research for cancer therapy in other laboratories around the world. – by Rob Volansky
Reference:
Fenstermaker RA, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-17-2778.
For more information:
Robert A. Fenstermaker, MD, can be reached at Roswell Park Comprehensive Cancer Center, Elm and Carlton streets, Buffalo, NY 14263; email: robert.fenstermaker@roswellpark.org.
Disclosures: Fenstermaker acknowledged the contributions of Michael Ciesielski, PhD, assistant professor in the department of neurosurgery at Roswell Park Comprehensive Cancer Center, who was critical in developing this approach and served as senior author on the most recent study. Ciesielski and Fenstermaker report being co-founders and equity shareholders of MimiVax LLC.