The Cancer Immunotherapy Laboratory

Our Vision

Our lab studies the unique immunology of human brain tumors. The lab aims to translate its scientific finding into clinical investigations in the field of cancer immunotherapy.
Our lab has developed a unique approach we call "Split Immunity", to immunologically treat brain tumors. This approach has already been utilized to treat two patients in a First in human (FIH) trial. Based on the results attained, additional twelve patients will be treated as part of an approved phase I/II trial that will soon commence.
For this project and other projects in the lab, we have developed an elaborate immunological toolbox consisting of advanced multicolor flow cytometry (up to 16 colors) coupled with transcriptomic tools. The developed toolbox has recently been licensed to a company named "Pyxis Diagnostics" aimed at identifying predictive biomarkers for cancer immunotherapy.
Using the labs' approach and methodologies, we study key immune cells within brain tumors. Cells such as dendritic cells, T cells, macrophages and microglia, serve different roles within the tumor-immune network and determine the fate of natural responses to the tumor as well as those responses induced by immunotherapy

Our Team

Dr Ilan Volovitz, Lab PI
Head, The Cancer Immunotherapy lab, The Neurosurgery dept (TASMC); The dept of microbiology and clinical immunology (TAU).

Dr. Tal Shahar, Lab PI

  • Dr Gilad Lehman
  • Antonina Polevikov
  • Kelly Lipczyc
  • Meytal Levinsky
  • Rotem Gershon
  • Gil Hasson

  • Dr Lital Gasri Plotnitsky, PhD
  • Dr Gil Diamant, PhD
  • Nati Shapira, MSc
  • Barak Bensimhon, MSc
  • Aharon Hagai, DMD, MSc
  • Oren Iny, MD
  • Idan Ben-Horin, MD
  • Tal Alter, MSc
  • Merav Lustgarten Bloch, MSc
  • Sara Amar, MSc
  • Salome Amouyal
  • Daniel Weber

Research

The lab has developed a unique approach to treat brain tumors that utilizes the discrepancy between the relatively weak immune surveillance inside the brain and the potent one outside it. The cells we use for vaccination are non-attenuated live autologous tumor cells. These live tumor cells, which grow uninhibitedly within the brain, are immunologically rejected when injected subcutaneously. The peripheral (subcutane) response to tumor cells spreads back to the brain, to kill the brain-residing tumor cells. This concept we termed ‘Split Immunity‘ was recently translated from animals to a First in Human (FIH) clinical trial on two recurrent glioblastoma (GBM) patients. The clinical investigation shall soon continue in a 12-patient, phase I/II clinical trial on recurrent, and then on newly-diagnosed glioblastoma patients.

milieu within human brain tumors

The lab has developed an extensive set of immune monitoring tools to monitor the immune milieu within brain-residing tumors. We also follow blood-borne cellular immune responses, which mirror therapy-induced changes occurring following immune intervention. We use multicolor (currently up to 16-colors) flow cytometry coupled with NGS tools. These tools, together, enable us to identify and study the function of key immune cells within brain tumors such as tumoral dendritic cells, T cells, macrophages, microglia and others

of tumor treating electric fields

The currently most effective FDA-approved treatment for newly diagnosed glioblastoma patients is Novocure’s OptuneTM. Optune generates alternating electric fields (TTFields) designed to kill dividing brain tumor cells. We study how this novel anti-cancer therapeutic modality affects tumor resident immune cells, such as T cells (the most important anti-tumoral effectors) and more recently, we study TTFields’ effects on tumoral dendritic cells. Dendritic cells are the most important cells guiding the immune system towards a potent response or to immune tolerance.

of colorectal cancers and biomarkers correlative with personal risk to develop these cancers

Our lab is taking part in a large project funded by the Israeli Science foundation’s Israel Precision Medicine Program (ISF-IPMP). We join forces with the labs of Profs Zvi Livneh and Moshe Oren from the Weizmann Institute of Science and with Prof Baruch Brenner from the Rabin Medical Center (Beilinson). Our part in the project is to identify immune-based biomarkers that can be used for early detection of colorectal cancer or that may correlate with the personal propensity for future development of these cancers

(CSN) within human tumors

The lab has developed a technology aimed at identifying network-level biomarkers, predictive of clinical responses to cancer immunotherapy. This technology uses an approach that combines advanced multicolor flow cytometry, next generation sequencing (NGS) tools and network immunology. A company based on our lab’s approach and technology named Pyxis Diagnostics has received the support of the Israeli Innovation Authority (IIA) via the VLX technological incubator, and via private biotech investors

From The Press-At tne media

Highlight Publications

Frequencies of four Tumor-infiltrating lymphocytes potently predict survival in glioblastoma, an immune desert.

Rotem Gershon, Antonina Polevikov, Yevgeny Karepov, Anatoly Shenkar, Idan Ben-Horin , Tal Alter Regev, Meytal Dror-Levinsky, Kelly Lipczyc, Lital Gasri-Plotnitsky, Gil Diamant , Nati Shapira , Barak Bensimhon , Aharon Hagai , Tal Shahar, Rachel Grossman, Zvi Ram, Ilan Volovitz. 

Neuro Oncol . 2023 Oct 23: doi: 10.1093/neuonc/noad204

T Cells Retain Pivotal Antitumoral Functions under Tumor-Treating Electric Fields. Diamant G, Simchony Goldman H, Gasri Plotnitsky L, Roitman M, Shiloach T, Globerson-Levin A, Eshhar Z, Haim O, Pencovich N, Grossman R, Ram Z, Volovitz I;  J Immunol. 2021; 207(2):709-719

Split immunity: immune inhibition of rat gliomas by subcutaneous exposure to unmodified live tumor cells. Volovitz, I., Marmor, Y., Azulay, M., Machlenkin, A., Goldberger, O., Mor, F., Slavin, S., Ram, Z., Cohen, I.R. & Eisenbach L, J Immunol. 2011, 187(10):5452-62

Immune Responses to SARS-CoV2 Mirror Societal Responses to COVID-19: Identifying Factors Underlying a Successful Viral Response Lev-Ari S, Rolnik B, Volovitz I. Biology 2021, 10(6), 485

Dendritic cells in context of human tumors-biology and experimental tools.  Volovitz I, Melzer S, Amar S, Bocsi J, Bloch M, Efroni S, Ram Z, Tárnok A . Int Rev Immunol. 2016 Mar 3;35(2):116-35

A non-aggressive, highly efficient, enzymatic method for dissociation of human brain-tumors and brain-tissues to viable single-cells Volovitz I, Shapira N, Ezer H, Gafni A, Lustgarten M, Alter T, Ben-Horin I, Barzilai O,  Shahar T, Kanner A, Fried I, Veshchev I, Grossman R and Ram Z.; BMC Neuroscience, 2016 17(1):30.

Exuberated numbers of tumor-specific T cells result in tumor escape Goldberger O, Volovitz I, Machlenkin A, Vadai E, Tzehoval E, Eisenbach L, Cancer Res. 2008 May 1;68(9):3450-7

Rh2-enriched Korean ginseng (Ginseng Rh2+) inhibits tumor growth and development of metastasis of non-small cell lung cancer.  Lev-Ari S , Starr AN , Vexler A , Kalich-Philosoph L , Yoo HS , Kwon KR , Yadgar M , Bondar E , Bar-Shai A , Volovitz I , Schwarz Y . Food Funct . 2021 ;12(17):8068-8077.

ImMucin: a novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors. Kovjazin R*, Volovitz I*, Kundel Y, Rosenbaum E, Medalia G, Horn G, Smorodinsky NI, Brenner B, Carmon L. Vaccine. 2011 Jun 24;29(29-30):4676-86. E. (* Equal contribution)

T cell vaccination induces the elimination of EAE effector T cells: Analysis using GFP-transduced, encephalitogenic T cells; Volovitz, I., Marmor Y, Mor F,  Fluegel A, Odoardi F, Eisenbach L, Cohen IR, J Autoimmun. 2010 Sep;35(2):135-44.

Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice; Machlenkin, A., R. Azriel-Rosenfeld, I. Volovitz, E. Vadai, A. Lev, A. Paz, O. Goldberger, Y. Reiter, E. Tzehoval, I. Benhar, and L. Eisenbach. 2006.. Cancer Immunol Immunother.56:217-26

Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity; Machlenkin, A., O. Goldberger, B. Tirosh, A. Paz, I. Volovitz, E. Bar-Haim, S. H. Lee, E. Vadai, E. Tzehoval, and L. Eisenbach. 2005.. Clin Cancer Res 11:4955.

Human CTL epitopes prostatic acid phosphatase-3 and six-transmembrane epithelial antigen of prostate-3 as candidates for prostate cancer immunotherapy . Machlenkin, A., A. Paz, E. Bar Haim, O. Goldberger, E. Finkel, B. Tirosh, I. Volovitz, E. Vadai, G. Lugassy, S. Cytron, F. Lemonnier, E. Tzehoval, and L. Eisenbach. 2005.. Cancer Res. 65:6435.

Prof Zvi Ram– selected publications

Efficacy and Safety of Tumor Treating Fields (TTFields) in Elderly Patients with Newly Diagnosed Glioblastoma: Subgroup Analysis of the Phase 3 EF-14 Clinical Trial. Ram Z, Kim CY, Hottinger AF, Idbaih A, Nicholas G, Zhu JJ. Front Oncol. 2021 Sep 27;11:671972.

P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression. Yeini E, Ofek P, Pozzi S, Albeck N, Ben-Shushan D, Tiram G, Golan S, Kleiner R, Sheinin R, Israeli Dangoor S, Reich-Zeliger S, Grossman R, Ram Z, Brem H, Hyde TM, Magod P, Friedmann-Morvinski D, Madi A, Satchi-Fainaro R. Nat Commun. 2021

Concurrent Tumor Treating Fields (TTFields) and Radiation Therapy for Newly Diagnosed Glioblastoma: A Prospective Safety and Feasibility Study. Bokstein F, Blumenthal D, Limon D, Harosh CB, Ram Z, Grossman R. Front Oncol. 2020 Apr 21;10:411.

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma. Paramasivam N, Hübschmann D, Toprak UH, Ishaque N, Neidert M, Schrimpf D, Stichel D, Reuss D, Sievers P, Reinhardt A, Wefers AK, Jones DTW, Gu Z, Werner J, Uhrig S, Wirsching HG, Schick M, Bewerunge-Hudler M, Beck K, Brehmer S, Urbschat S, Seiz-Rosenhagen M, Hänggi D, Herold-Mende C, Ketter R, Eils R, Ram Z, Pfister SM, Wick W, Weller M, Grossmann R, von Deimling A, Schlesner M, Sahm F. Acta Neuropathol. 2019 Aug;138(2):295-308.

Reverting the molecular fingerprint of tumor dormancy as a therapeutic strategy for glioblastoma. Tiram G, Ferber S, Ofek P, Eldar-Boock A, Ben-Shushan D, Yeini E, Krivitsky A, Blatt R, Almog N, Henkin J, Amsalem O, Yavin E, Cohen G, Lazarovici P, Lee JS, Ruppin E, Milyavsky M, Grossman R, Ram Z, Calderón M, Haag R, Satchi-Fainaro R.. FASEB J. 2018 Jun 1:fj201701568R

Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R. JAMA Oncol. 2018 Apr 1;4(4):495-504

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. Stupp R, Taillibert S, Kanner A, Read W, Steinberg DM, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran DD, Brem S, Hottinger AF, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Burna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. JAMA. 2017 Dec 19;318(23):2306-2316.

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome Ferber S, Tiram G, Sousa-Herves A, Eldar-Boock A, Krivitsky A, Scomparin A, Yeini E, Ofek P, Ben-Shushan D, Vossen LI, Licha K, Grossman R, Ram Z, Henkin J,  Ruppin E, Auslander N, Haag R, Calderón M, Satchi-Fainaro R.. Elife. 2017 Oct 4;6. pii: e25281.

Post Hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A™ system versus best physician’s choice chemotherapy. Kanner AA, Wong ET, Villano JL, Ram Z; EF-11 Investigators.. Semin Oncol. 2014 Oct;41 Suppl 6:S25-34

European Association for Neuro-Oncology (EANO) Task Force on Malignant Glioma.. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A,Cohen-Jonathan-Moyal E, Frappaz D, Henriksson R, Balana C, Chinot O, Ram Z, Reifenberger G, Soffietti R, Wick W; Lancet Oncol. 2014 Aug;15(9):e395-403

Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Westphal M, Ylä-Herttuala S, Martin J, Warnke P, Menei P, Eckland D, Kinley J, Kay R, Ram Z; ASPECT Study Group.. Lancet Oncol. 2013 Aug;14(9):823-33.
}