Prof. Yona Keisari

Professor Emeritus, Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, Tel Aviv University

Associate Editor, Mediators of Inflammation

Treasurer, International Cancer Microenvironment Society    

Education

1966-1971	M.Sc., Microbiology & Immunology	Tel Aviv University
1971-1976	Ph.D., Immunology	Tel Aviv University
1976-1978	Postdoctoral Fellow, Department of Tumor Immunology	National Cancer Inst. NIH, Bethesda, USA.

 

Development of cancer treatments integrating radiotherapy or electrochemical ablation and immunotherapy

Cancer is currently the most devastating chronic disease affecting humankind. Today solid malignant tumors are mainly treated by surgery and/or radiotherapy to eradicate the local primary lesion, and chemotherapy, that is administered mainly to destroy remaining local or distant malignant cells. In spite of the advancement in preventing and treating cancer, morbidity and mortality remain high, especially in cases when tumors are highly metastatic, or cannot be completely removed. The main goal of our research projects is to develop in situ tumor ablation treatments of primary tumors and incorporate them with systemic chemotherapy and immuno-stimulatory agents, into combined treatment protocols.

 

In order to achieve efficient primary tumor ablation we developed two novel and powerful treatment modalities for solid cancer, which can be used instead or in combination with surgery. The first treatment, developed with Prof. Rafi Korenstein (Dept. Physiology & Pharmacology), is base on the use of intratumoral unipolar pulsed electric currents for the ablation (ECTA) of solid primary tumors. ECTA can be enforced by the concomitant use of chemotherapeutic agents in the treatment of tumors. The second cancer treatment, developed with Prof. Itzhak Kelson (School of Physics & Astronomy), is based on insertion into the tumor of radioactive wires that spread in the tumor alpha emitting atoms and can also be augmented by chemotherapy.

 

Our teams proved that these treatment modalities effectively destroy primary tumors, and reduce the metastatic load in experimental animal and human cancer models of melanoma, breast, colon, prostate, pancreas, lung, and squamous cell carcinomas. We found that in situ ablation of primary antigenic tumors led to the activation of immunological reactions, destroying remaining malignant cells in the primary tumor as well as in distant metastases. Immunopharmacological methods aimed to stimulate the patient's immune response against the cancer after local tumor ablation can make use of several approaches and we currently study the following: (1) Immunostimulation by adjuvants such as the oligonucleotides, CpG, which enforce weak immune reactions. (2) Inhibition of immunosuppressive mechanisms such as T-regulatory and Myeloid Derived Suppressor cells (MDSC). (3) Combination with inhibitors of immunological checkpoints such as anti CTLA-4 or anti PDL1/PD1.

 

 

Domankevich, V., Cohen, A., Efrati, M., Schmidt, M., Rammensee, H-G., Nair, S.S., Tewari, A., Kelson, I., Keisari^, Y. Combining Alpha Radiation-Based Brachytherapy with Immunomodulators Promotes Complete Tumor Regression in Mice via Tumor-Specific Long-Term Immune Response. Cancer Immunol Immunother. 2019; 68, 1949-1958. https://doi.org/10.1007/s00262-019-02418-5

 

Bellia, S.R., Feliciani, G., Del Duca, M., Monti, M., Turri, V., Sarnelli, A., Romeo, A., Kelson, I., Keisari, Y., Popovtzer, A., Ibrahim, T., Paganelli, G., Stanganelli, I. Clinical evidence of abscopal effect in cutaneous squamous cell carcinoma (cSCC) treated with Diffusing alpha emitters Radiation Therapy (DaRT): a case report. J. Contemp. Brachytherapy 2019; 11, 5: 449–457. DOI: https://doi.org/10.5114/jcb.2019.88138

 

Popovtzer, A., Rosenfeld, E., Mizrachi, A., Bellia, SR., Ben-Hur, R., Feliciani, G., Sarnelli, MA., Arazi, L., Deutch, L., Kelson, I., Keisari, Y. Initial Safety and Tumor Control Results from a “First-in-Human” Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck. Int. J. Rad. Oncol. Biol. & Phys. 2020, 106, 571-578. doi: 10.1016/j.ijrobp.2019.10.048.

 

Domankevich, V., Efrati, M/. Schmidt, M., Glikson, E., Mansour, F., Shai, A., Cohen, A., Zilberstein, Y., Flaisher, E., Galalae, R., Kelson, I., Keisari, Y.^. RIG-I-like Receptor Activation Synergizes with Alpha-Radiation to Promote Systemic Antitumor Immunity, Solid Tumor Rejection and Metastases Clearance in Mice. Front. Oncology. in press. 19-MAY-2020.

 

Shoval A, Tepper M, Tikochkiy J, Ben Gur L, Markovich G, Keisari Y, Gannot I. Magnetic Nanoparticles Based Acoustical Detection and Hyperthermic Treatment of Cancer, in vitro and in vivo Studies. J. Nanophotonics. 10:036007, 2016.

 

Confino H, Schmidt M, Efrati M, Hochman I, Umansky V, Kelson I, Keisari Y. Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG. First online: 06 August 2016.

 

Confino, H., Hochman, I., Efrati, M., Schmidt, M., Umansky, V., Kelson, I., Keisari, Y. Tumor ablation by intratumoral Ra-224 loaded wires induces anti-tumor immunity against experimental metastatic tumors. Cancer Immunol Immunother. 2014 64:191-199.

 

Milrot, E., Jackman, A., Flescher, E., Gonen, P., Kelson, I., Keisari, Y., Sherman, L. Enhanced killing of cervical cancer cells by combinations of methyl jasmonate with cisplatin, X or alpha radiation. Invest. New Drugs. 31:333-44, 2013.

 

Reitkopf-Brodutch, S., Confino, H., Schmidt, M., Cooks, T., Efrati, M., Arazi, L., Rath-Wolfson, L., Marshak, G., Kelson, I., Keisari Y. Ablation of experimental colon cancer by intratumoral 224Radium Loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy. Int J Radiation Biol. 2014 2:1-15.

 

Keisari, Y., Hochman, I., Confino, H., Korenstein, R., Kelson, I. Activation of local and systemic antitumor immune responses by ablation of solid tumors with intra-tumoral electrochemical or alpha radiation treatments. Cancer Immunol Immunother. 63:1-9, 2014.

 

Tepper, M., Shoval, A., Hoffer, O., Confino, H., Kelson, I., Keisari, Y., Gannot. I. Thermographic investigation of tumor size, and its correlation to tumor relative temperature, in mice with transplantable solid breast carcinoma. J Biomed Optics. 18:111410, 2013.

 

Horev-Drori, G., Cooks, T., Bittan, H., Lazarov, E., Schmidt, M., Arazi, L., Efrati, M., Kelson, I., Keisari, Y. Local control of malignant pancreatic tumors by a combined treatment with intratumoral 224Radium-loaded wires releasing alpha-emitting atoms and chemotherapy. Transl. Res. 159:32-41; 2012.

 

Lazarov, E., Arazi, L., Efrati, M., Cooks, T., Schmidt, M., Keisari, Y., Kelson, I. Comparative in vitro microdosimetric study of murine and human-derived cancer cells exposed to alpha particles. Radiat. Res. 177: 280–287; 2012.

 

Greenberg, E., Hershkovitz, L., Hajdu, S., Nemlich, Y., Itzhaki, O., Ortenberg, R., Gefen, N., Edry, L., Barschak, I., Keisari, Y., Besser, M.J., Schachter, J., Shomron, N., Markel, G. Regulation of cancer aggressive features in melanoma cells by microRNA molecules. Plos one. 2011 Apr 25;6(4):e18936

 

Cafri, G., E. Amram, G. Rinot, G. Koifman, S. Fishman, Y. Keisari, E. Tzehoval, L. Eisenbach, A. Margalit, G. Gross. Coupling presentation of MHC class I peptides to constitutive activation of antigen-presenting cells through the product of a single gene. Int Immunol. 23: 453-461; 2011.

 

Arazi L., Cooks T., Schmidt M., Keisari Y., Kelson I. Treatment of solid tumors by alpha emitters released from 224Ra-loaded sources – internal dosimetry analysis. Phys. Med. Biol. 55: 1203-1218; 2010.

 

Keisari, Y., Korenstein, R. Anti-tumoral effects of pulsed low electric field enhanced chemotherapy: lessons from experimental malignant tumors. In: Electroporation in laboratory and clinical investigations. E. P. Spugnini and A. Baldi, eds. Nova Science Publishers, Inc. Hauppauge, NY., 2009.

 

Cooks, T., Schmidt, M., Bittan, H., Lazarov, E., Arazi, L., Kelson, I., and Keisari, Y. Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with Radium-224. Int J Radiat Oncol Biol Phys. 74: 966-973, 2009.

 

Markel, G., Cohen-Sinai, T., Besser M.J., Oved, K., Itzhaki, O., Seidman, R., Fridman, E., Treves, A.J., Keisari, Y., Dotan, Z., Ramon, J., Schachter, J. Preclinical evaluation of adoptive cell therapy for patients with metastatic renal cell carcinoma. Anticancer Res. 29: 145-154, 2009.

 

Cooks, T., Arazi, L., Efrati, M., Schmidt, M., Marshak, G., Kelson, I., Keisari, Y. Interstitial wires releasing diffusing alpha-emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma bearing mice. Cancer 115: 1791-1801, 2009.

 

Sahly, H., Keisari, Y., Ofek, I. Manno(Rhamno)biose-containing capsular polysaccharides of Klebsiella pneumoniae enhance opsono-stimulation of human polymorphonuclear leukocytes. J. Innate Imm. 1: 136-144, 2009.

 

Sahly, H., Y. Keisari, E. Crouch, N. Sharon, I. Ofek. Recognition of bacterial surface polysaccharides by lectins of the innate immune system and virulence: the case of pulmonary pathogens. Infect. Immun. 76: 1322-1332, 2008.

 

Cooks, T., L. Arazi, M. Schmidt, G. Marshak, I. Kelson, Y. Keisari. Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Int. J. Cancer 122:1657-1664,  2008.

 

Arazi, L., T. Cooks, M. Schmidt, Y. Keisari, I. Kelson. Treatment of solid tumours by interstitial release of recoiling short-lived alpha emitters. Phys. Med. Biol, 52: 5025-5042: 2007.

 

Lucas, R., Y. Keisari. Innovative cancer treatments that augment radiotherapy or chemotherapy by the use of immunotherapy or gene therapy. Recent Patents on Anti-Cancer Drug Discovery, 1: 201-208, 2006.

 

Plotnikov, A., B. Niego, R. Ophir, R. Korenstein, Y. Keisari. Effective treatment of mouse metastatic prostate cancer by low electric field enhanced chemotherapy. The Prostate, 66: 1620-1630,  2006.

 

Kostina E, Ofek I, Crouch E, Friedman R, Sirota L, Klinger G, Sahly H, Keisari Y. Noncapsulated Klebsiella pneumoniae bearing mannose-containing O antigens is rapidly eradicated from mouse lung and triggers cytokine production by macrophages following opsonization with surfactant protein D. Infect Immun. 2005;73(12):8282-90.

 

Plotnikov A, Tichler T, Korenstein R, Keisari Y. Involvement of the immune response in the cure of metastatic murine CT-26 colon carcinoma by low electric field-enhanced chemotherapy. Int J Cancer. 2005;117(5):816-24.

 

Keisari Y. Human mononuclear phagocytes in tissue culture. Methods Mol Med. 2005;107:137-45.

 

 

Chapters
Keisari Y. Tumor abolition and antitumor immunostimulation by physico-chemical tumor ablation. Frontiers Biosc. Landmark, 22: 310-347, 2017. In press.

 

Keisari Y., Korenstein R. In-situ ablation of solid tumors by electric forces and its effect on the tumor microenvironment and anti-tumor immunity. In: Tumor Ablation: effects on systemic and local anti-tumor immunity and on other tumor-microenvironment interactions. Y. Keisari, Ed. Springer, 2013, Ch. 8, pp. 133-153.

 

Keisari, Y., Korenstein, R. Anti-tumoral effects of pulsed low electric field enhanced chemotherapy: lessons from experimental malignant tumors. In: Electroporation in laboratory and clinical investigations. E. P. Spugnini and A. Baldi, eds. Nova Science Publishers, Inc. Hauppauge, NY, USA, 2012, Ch. 9, pp. 178-204.

 

 

Books
Keisari Y. Tumor Ablation: effects on systemic and local anti-tumor immunity and on other tumormicroenvironment interactions. Springer, 2013.