Oncolytic Virus Research Laboratory

Overview

Oncolytic immunotherapy is a cancer treatment that uses the viruses that mediate antitumor activity to induce immunogenic cell death and generate an immunity against tumors.

The Oncolytic Virus Laboratory at Massachusetts General Hospital is using animal models and human clinical trials, with a particular focus on the herpes simplex virus, to better understand and improve oncolytic immunotherapy.

The goals of the Oncolytic Virus Lab are to:

• Understand how oncolytic viruses kill tumor cells
• Establish the mechanism(s) of oncolytic virus-induced tumor immunity
• Identify strategies to increase the effectiveness of oncolytic immunotherapy
• Conduct clinical studies to support the therapeutic potential of oncolytic immunotherapy
• Discover and validate predictive biomarkers of oncolytic immunotherapy

Leadership

The Oncolytic Virus Lab is directed by Howard Kaufman, MD, FACS, a surgeon in the Mass General Division of Gastrointestinal and Oncologic Surgery. Dr. Kaufman is a physician-scientist and leading authority on oncolytic tumor immunotherapy, pioneering the first oncolytic virus therapy for the treatment of melanoma and the first immunotherapy for treating Merkel cell carcinoma.

Research Projects

Biomarkers of Oncolytic Immunotherapy

The importance of predictive biomarkers to better select appropriate patients for immunotherapy as well as for identifying putative mechanisms of resistance has been emphasized as a high priority for the field. Ongoing projects are utilizing patient-derived biospecimens to explore potential intracellular and peripheral biomarkers of response. In addition, we are employing novel technologies to explore genomic, proteomic and metabolomic factors that influence the therapeutic response to oncolytic virus immunotherapy. We work closely with the Sara Pai, MD, and Ryan Sullivan, MD, labs on these projects.

Combination Oncolytic Immunotherapy

A major focus of the lab is to develop innovative combination strategies wherein oncolytic viruses are used to induce lymphocyte recruitment and activation to sites of tumor growth and optimize combination regimens. This has included both animal models and human clinical trials. We established a role for combination of HSV-1 oncolytic virus with immune checkpoint blockade in clinical melanoma studies. In addition, we recently identified a new pathway where MEK inhibition augmented oncolytic virus replication and increased sensitivity of tumors to PD-1 blockade. These findings are being pursued in new clinical trials for patients with melanoma and other types of solid tumors.

Oncolytic Viruses Killing of Tumor Cells

How does oncolytic HSV-1 kill tumor cells and induce immunogenic cell death? Studies in the lab have focused on the role of apoptosis and other forms of cell death, such as autophagy, in mediating cell death. We have also demonstrated the release of danger-associated molecular pattern (DAMP) factors following oncolytic virus infection. In addition, we have explored how specific elements of the antiviral machinery, such as STING, can influence viral replication and induction of host immune responses.

Oncolytic Virus-induced AntiTumor Immunity

The clearance of tumor depends on the balance between anti-viral and anti-tumor immunity. The lab has established numerous models to explore how innate and adaptive immunity responds to oncolytic immunotherapy. We are also exploring the mechanisms of local immunity at sites to intratumoral virus delivery compared to induction of systemic anenestic responses that occur at distant, uninjected tumor sites.

Publications

1. Everett, A.S., Pavlidakey, P.G., Contreras, C.M., De Los Santos, J.F., McKee, S.B., Kaufman, H.L. and Conry, R.M. Chronic granulomatous dermatitis induced by talimogene laherparepvec therapy of melanoma metastases. J. Cutaneous. 45(1):48-53, 2017. PMID: 28940544
2. Gartrell, R., Marks, D., Hart, T., Li, G., Davari, D., Askin, K., Esancy, C., Stack, E.C., Jia, D.T., Armenta, P., Fu, Y., Izaki, D., Taback, B., Kaufman, H.L., Drake, C., Horst, B. and Saenger, Y. Quantitative analysis of immune infiltrates in primary melanoma. Cancer Immunol. Res. 6(4):481-493, 2018. PMID: 29467127
3. Wagner, J., Kline, L., Zhou, L., Campbell, K.S., MacFarlane, A.W., Olszanski, A.J., Hensley, H.H., Ross, E.A., Ralff, M.D., Zloza, A., Chesson, C.B., Newman, J.H., Kaufman, H.L., Bertino, J., Stein, M.N. and El-Deiry, W. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment. J. Clin. Invest. 128(6):2325-2338, 2018. PMID: 29533922
4. Chesney, J., Puzanov, I., Collichio, F., Singh, P., Milhem, M., Glaspy, J., Hamid, O., Ross, M., Friedlander, P., Garbe, C., Logan, T., Hauschild, A., Lebbe, C., Chen, L., Kim, J.J., Gansert, J., Andtbacka, R.H.I. and Kaufman, H.L. Randomized, open-label phase 2 study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab in patients with advanced, unresectable melanoma. J. Clin. Oncol. 36(17):1658-1667, 2017. PMID: 28981385
5. Bommareddy, P.K., Aspromonte, S., Zloza, A., Rabkin, S.D. and Kaufman, H.L. MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation. Science Transl. Med, 2018
6. Puzanov, I., Milhem, M. M., Minor, D., Hamid, O., Li, A., Chen, L., Chastain, M., Gorski, K.S., Anderson, A., Chou, J., Kaufman, H.L. and Andtbacka, R.H.I. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J. Clin. Oncol. 34(22):2619-2626, 2016. PMID: 27298410
7. Kohlhapp, F.J., Huelsmann, E.J., Lacek, A.T., Schenkel, J.M., Broucek, J.R., Goldufsky, J.W., Hughes, T., Zayas, J.P., Dolobuzino, H., Sowell, R.T., Kuehner, R., Burd, S., Kubasiak, J., Nabatiyan, A., Marshall, S., Bommareddy, P., Li, S., Shafikhani, S., Marzo, A.L., Guevara-Patino, J.A., Lasfar, A., Thomas, P.G., Kaufman, H.L. and Zloza, A. Non-oncogenic acute viral infections disrupt anti-cancer responses and lead to accelerated cancer-specific host death. Cell Rep. 17(4):957-965, 2016. PMID: 27760326
8. Kaufman, H.L., Andtbacka, R.H.I., Collichio, F.A, Wolf, M., Zhao, Z., Shilkrut, M., Puzanov, I., Moore, D. and Ross, M. Clinical benefits associated with durable response in patients with unresected stage IIIB/C/IV melanoma treated with talimogene laherparepvec (T-VEC) or GM-CSF in the Phase 3 OPTiM trial. J. Immunother. Cancer. 5(1):72, 2017. PMID: 28923101
9. Kaufman, H.L., Andtbacka, R.H.I., Collichio, F.A., Wolf, M., Zhaq, Z., Shilkrut, M., Puzanov, I. and Ross, M. Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. J. Immunother. Cancer. 5(1):72, 2017. PMID: 28923101
10. Faries, M.B., Mozzillo, N., Kashani-Sabet, M., Thompson, J.F., Kelley, M.C., DeConti, R.C., Lee, J.E., Huth, J.F., Wagner, J., Dalgleish, A., Pertschuk, D., Nardo, C., Stern, S., Elashoff, R., Gammon, G., Morton, D.L., Smithers, M., Hughes, M., Coventry, B.J., Shapiro, J., McArthur, G., Buzaid, A., Miller, W., Schadendorf, D., Garbe, C., Kaatz, M., Peter, R.U., Terheyden, P., Redmond, P., Schneebaum, S., Testori, A., Santinami, M., Hoekstra, H.J., McCrystal, M., Dummer, R., Hersh, E., Anderson, C., McMasters, K., Schuchter, L., Karakousis, C.P., Kraybill, W., Gonzalez, R., Byrd, D., Ollila, D., Walker, M., Borden, E., Demierre, M.F., Noyes, D., Reintgen, D., Riley, L., Yao, K., Kaufman, H., Leming, P., Levine, E., Ready, N., Sarna, G., Sharfman, W., Dillman, R., Estes, N., Hutchins, L., Pecora, A., Richart, J., Rothschild, N,, Vetto, J., Wanebo, H., Warso, M., Carp, N., Elias, G., Greene, M., Hyams, D., Lutzky, J., Polikoff, J., Sardi, A., Senecal, F. Long-term survival after complete surgical resection and adjuvant immunotherapy for distant melanoma metastases. Ann. Surg. Oncol. 24(13):3991-4000, 2017. PMID: 29019177

Recent Reviews From the Lab

1. Bommareddy, P.K., Shettigar, M. and Kaufman, H.L. Integrating oncolytic viruses in combination cancer immunotherapy. Nature Rev. Immunol. doi: 10.1038/s41577-018-0014-6. [Epub ahead of print], 2018. PMID:29743717
2. Ott, P.A., Hodi, F.S., Kaufman, H.L., Wigginton, J.M. and Wolchok, J.D. Combination immunotherapy – a road map. J Immunother. Cancer. 5:16. doi: 10.1186/s40425-017-0218-5., 2017. PMID: 28239469
3. Bommareddy, P.K., Patel, A., Hossain, S. and Kaufman, H.L. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am. J. Clin. Dermatol. 18(1):1-15, 2017. PMID: 27988837
4. Rehman, H., Silk, A.W., Kane, M.P. and Kaufman, H.L. Into the clinic: talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J. Immunother. Cancer. 4:53, 2016. PMID: 27660707
5. Dharmadhikari, N., Mehnert, J. and Kaufman, H.L. Oncolytic virus therapy for melanoma. Curr. Treatment Options Oncol. 16(3):326, 2015. PMID: 25777572
6. de Vries, C.R., Kaufman, H.L. and Lattime, E.C. Oncolytic viruses: focusing on the tumor microenvironment. Cancer Gene Ther. 22(4):169-71, 2015. PMID: 25721204
7. Kaufman, H.L., Kohlhapp, F.J. and Zloza, A. Oncolytic viruses: a new class of immunotherapy drugs. Nature Rev. Drug Discovery. 14(9):642-663, 2015. PMID: 26323545
8. Kohlhapp, F., Zloza, A. and Kaufman, H.L. talimogene laherparepvec (T-VEC) as cancer immunotherapy. Drugs Today. 51(9):549-558, 2015.PMID: 26488034
9. Bommareddy, P.K., Peters, C., Rabkin, S. and Kaufman, H.L. Oncolytic herpes simplex viruses as a paradigm for the treatment of cancer. Ann. Rev. Cancer Biol. 2:155-173, 2018. https://www.annualreviews.org/doi/10.1146/annurev-cancerbio-030617-050254