Exploring therapeutic potential of stem cell regeneration in the event of radiation insult
Exposure to high doses of ionizing radiation in the event of therapeutic, accidental or intentional incident such as nuclear/radiological warfare can lead to debilitating injuries to multiple organs resulting in death within days depending on the amount of radiation dose and the quality of radiation. Unfortunately, there is not a single FDA-licensed drug approved against acute radiation injury.

Radiation damage to multiple organs often described as multiple organ dysfunction syndrome (MODS) or acute radiation syndrome (ARS) results from rapid depletion of radiosensitive cells, these cells are usually the stem or progenitor cells with high proliferative capacity; naturally, bone marrow stem cells (BMSC), and intestinal stem cells (ISC), which are extremely critical in maintaining a pool of peripheral blood cells and in maintaining villi for the absorption of nutrients are highly sensitive to radiation. One of the most efficient ways of rescuing MODS is to administer fresh cells that can repair, support and/or replace the damaged cells and repopulate the damaged tissue with healthy cells. The Rad-Stem Center for Medical Countermeasures against Radiation (RadStem CMCR) program at Einstein is developing stem cell-based therapies to treat acute radiation syndrome (ARS) that results from radiation injury.

Radiation-induced gastrointestinal syndrome (RIGS) results from a combination of direct damage to intestinal crypt and endothelial cells, and subsequent loss of the mucosal barrier leading to microbial infection, septic shock and systemic inflammatory response syndrome (SIRS). Currently, there is no treatment for RIGS in clinic. Irradiation induces apoptosis of crypt ISC, endothelial cells and enterocytes within hours. Acute loss of cells in situ requires rapid compensation of their functions and this is best achieved using cell replacement therapies. We are interested in exploring intestinal regenerative therapy with a combination of systemic administration of growth factors and cell replacement therapy to salvage Gl function post-radiation exposure. We are testing combinations of: a) intestinal stem cell growth factor, R-spondinl (R-spol), b) TLR ligands, and c) transplantation of bone marrow-derived endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) to restore IR-damaged ISC niche, protect against IR-induced cell death and provide growth signals for host ISC regeneration, thus providing protection and mitigation from RIGS.

Preparative live irradiation for hepatocyte transplant in acute liver injury and cirrhosis
Hepatocyte transplantation (HT) is a very attractive alternative to liver transplant in the treatment of both inherited and acquired liver diseases. However, benefits of this procedure are currently limited by the inability of the transplanted hepatocytes to proliferate in the host liver, and lack of a noninvasive method to evaluate the repopulation of transplanted hepatocytes in the liver. In order to develop a clinically feasible protocol for HT, we are exploring preparative hepatic irradiation (HIR) for liver repopulation (in place of liver transplant) to deplete host hepatocytes and permit preferential proliferation of the engrafted donor cells in response to hepatic mitotic stimuli.  Our lab was the first one to demonstrate that preparative HIR and partial hepatectomy (PH), followed by HT results in the replacement of virtually all host hepatocytes by the transplanted non-irradiated hepatocytes in 12 weeks. We are interested in using inducible pluripotent stem cells (iPSC)- derived hepatocytes following highly focused irradiation of the damaged liver in place of a liver transplant. We are also interested in exploring non-invasive biomarkers to validate that the transplanted hepatocytes can efficiently replace host hepatocytes upon liver irradiation.

Cancer Immunotherapy
Radiation therapy (RT) has been used as a standard treatment modality for many solid tumors. While tumoricidal properties of RT are instrumental for standard clinical application, irradiated tumors can potentially serve as a source of tumor antigens in vivo, where dying tumor cells would release various tumor antigens slowly over time. Using different in vitro and in vivo tumor models we, and others, demonstrated that RT enhances oxidative stress, and augments the release of necessary activating signals for DC such as endogenous danger associated molecular pattern (DAMP) molecules from irradiated cells. These RT-mediated processes lead to an increase antigenecity of irradiated cells which augments antigen presentation leading to an effective anti-tumoral immune responses. However the underlying mechanism of this processes has still to be determined.

Over the last years we have been interested in designing novel tumor vaccines that amplify the tumor immune response using conventional and exploratory cancer therapies. In particular we are focusing on evaluating the immunogenic properties of radiation therapies and determine how immunotherapeutic molecules can synergize with RT in boosting immune cells cell function. We are also interested in exploring therapeutic effect of ultrasound therapy in the treatment of solid tumor. Our recent work on use of Listeria-based vaccine therapy in combination of RT shows that this strategy is more effective than RT alone.

Immunomodulation of radiation therapy: Radiation-enhanced tumor vaccines

1. Ahmed MM, Guha C, Hodge JW, Jaffee E. Immunobiology of Radiotherapy: New Paradigms. Radiat Res. 2014, Aug;182(2):123-5
2. Almo SC, Guha C. Considerations for Combined Immune Checkpoint Modulation and Radiation Treatment. Radiat Res. 2014, Aug;182(2):230-8
3. Kawashita Y, Deb NJ, Garg M, Kabarriti R, Alfieri A, Takahashi M, Roy-Chowdhury J, Guha C. An Autologous In Situ Tumor Vaccination Approach for Hepatocellular Carcinoma. Flt3 Ligand Gene Transfer Increases Antitumor Effects of a Radio-Inducible Suicide Gene Therapy in an Ectopic Tumor Model. Radiat Res. 2014 Aug;182(2):201-10
4. Bernstein, Michael B; Garnett, Charlie T; Zhang, Huogang; Velcich, Anna; Wattenberg, Max M; Gameiro, Sofia R; Kalnicki, Shalom; Hodge, James W; Guha, Chandan. Radiation-induced modulation of costimulatory and coinhibitory T-cell signaling molecules on human prostate carcinoma cells promotes productive antitumor immune interactions. Cancer biotherapy & radiopharmaceuticals, 2014 May; 29 (4):153-61
5. Ahmed MM, Hodge JW, Guha C, Bernhard EJ, Vikram B, Coleman CN. Harnessing the potential of radiation-induced immune modulation for cancer therapy. Cancer Immunol Res. 2013 Nov;1(5):280-4
6. Gameiro SR, Higgins JP, Dreher MR, Woods DL, Reddy G, Wood BJ, Guha C, Hodge JW. Combination therapy with local radiofrequency ablation and systemic vaccine enhances antitumor immunity and mediates local and distal tumor regression. PLoS One. 2013 Jul 24;8(7)
7. Zhang, Huagang; Liu, Laibin; Yu, Dong; Kandimalla, Ekambar R; Sun, Hui Bin; Agrawal, Sudhir; Guha, Chandan. An in situ autologous tumor vaccination with combined radiation therapy and TLR9 agonist therapy. PloS one, 2012; 7 (5)
8. Hannan, Raquibul; Zhang, Huagang; Wallecha, Anu; Singh, Reshma; Liu, Laibin; Cohen, Patrice; Alfieri, Alan; Rothman, John; Guha, Chandan. Combined immunotherapy with Listeria monocytogenes-based PSA vaccine and radiation therapy leads to a therapeutic response in a murine model of prostate cancer. Cancer immunology, immunotherapy: CII, 2012 Dec; 61 (12):2227-38

Stem cell based therapy for radiation injury

1. Benderitter, Marc; Caviggioli, Fabio; Chapel, Alain; Coppes, Robert P; Guha, Chandan; Klinger, Marco; Malard, Olivier; Stewart, Fiona; Tamarat, Radia; Luijk, Peter Van; Limoli, Charles L. Stem Cell Therapies for the Treatment of Radiation-Induced Normal Tissue Side Effects. Antioxidants & redox signaling, 2014, Jul 10;21(2):338-55
2. Zachman, Derek K; Leon, Ronald P; Das, Prerna; Goldman, Devorah C; Hamlin, Kimberly L; Guha, Chandan; Fleming, William H. Endothelial cells mitigate DNA damage and promote the regeneration of hematopoietic stem cells after radiation injury. Stem cell research, 2013 Nov; 11 (3):1013-21
3. Saha, Subhrajit; Bhanja, Payel; Liu, Laibin; Alfieri, Alan A; Yu, Dong; Kandimalla, Ekambar R; Agrawal, Sudhir; Guha, Chandan, ‘TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome’; PloS one, 2012; 7 (1)
4. Saha, Subhrajit; Bhanja, Payel; Kabarriti, Rafi; Liu, Laibin; Alfieri, Alan A; Guha, Chandan,. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PloS one, 2011; 6 (9)
5. Bhanja P, Saha S, Kabarriti R, Liu L, Roy-Chowdhury N, Roy-Chowdhury J, Sellers RS, Alfieri AA, Guha C. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS One. 2009 Nov 24;4(11)

Preparative irradiation to facilitate liver cell repopulation and stem cell engraftment in vivo

1. Vainshtein, Jeffrey M; Kabarriti, Rafi; Mehta, Keyur J; Roy-Chowdhury, Jayanta; Guha, Chandan. Bone Marrow-Derived Stromal Cell Therapy in Cirrhosis: Clinical Evidence, Cellular Mechanisms, and Implications for the Treatment of Hepatocellular Carcinoma. International journal of radiation oncology, biology, physics, 2014 Jul 15; 89 (4):786-803
2. Vainshtein, Jeffrey M; Kabarriti, Rafi; Mehta, Keyur J; Roy-Chowdhury, Jayanta; Guha, Chandan. Bone Marrow-Derived Stromal Cell Therapy in Cirrhosis: Clinical Evidence, Cellular Mechanisms, and Implications for the Treatment of Hepatocellular Carcinoma. International journal of radiation oncology, biology, physics. 2014 Jul 15; 89 (4):786-803
3. Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V; Deutsch, Melvin; Quader, Mubina A; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro; Roy-Chowdhury, Jayanta; Locker, Joseph; Abe, Michio; Enke, Charles A; Baranowska-Kortylewicz, Janina; Solberg, Timothy D; Guha, Chandan; Fox, Ira J. A nonhuman primate model of human radiation-induced venocclusive liver disease and hepatocyte injury. International journal of radiation oncology, biology, physics, 2014 Feb 1; 88 (2):404-11
4. Miyazaki, Kensuke; Yamanouchi, Kosho; Sakai, Yusuke; Yamaguchi, Izumi; Takatsuki, Mitsuhisa; Kuroki, Tamotsu; Guha, Chandan; Eguchi, Susumu, ‘Construction of liver tissue inýývivo with preparative partial hepatic irradiation and growth stimulus: investigations of less invasive techniques and progenitor cells’; The Journal of surgical research. 2013 Dec; 185 (2):889-95
5. Puppi, Juliana; Strom, Stephen C; Hughes, Robin D; Bansal, Sanjay; Castell, Jose V; Dagher, Ibrahim; Ellis, Ewa C S; Nowak, Greg; Ericzon, Bo-Goran; Fox, Ira J; Gomez-Lechon, M Jose; Guha, Chandan; Gupta, Sanjeev; Mitry, Ragai R; Ohashi, Kazuo; Ott, Michael; Reid, Lola M; Roy-Chowdhury, Jayanta; Sokal, Etienne; Weber, Anne; Dhawan, Anil, ‘Improving the techniques for human hepatocyte transplantation: report from a consensus meeting in London’; Cell transplantation. 2012; 21 (1):1-10
6. Zhou, Hongchao; Dong, Xinyuan; Kabarriti, Rafi; Chen, Yong; Avsar, Yesim; Wang, Xia; Ding, Jianqiang; Liu, Laibin; Fox, Ira J; Roy-Chowdhury, Jayanta; Roy-Chowdhury, Namita; Guha, Chandan. Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. PloS one. 2012; 7 (10)
7. Ding, Jianqiang; Yannam, Govardhana R; Roy-Chowdhury, Namita; Hidvegi, Tunda; Basma, Hesham; Rennard, Stephen I; Wong, Ronald J; Avsar, Yesim; Guha, Chandan; Perlmutter, David H; Fox, Ira J; Roy-Chowdhury, Jayanta. Spontaneous hepatic repopulation in transgenic mice expressing mutant human ýý1-antitrypsin by wild-type donor hepatocytes. The Journal of clinical investigation, 2011 May; 121 (5):1930-4
8. Soltys, Kyle A; Soto-Gutierrez, Alejandro; Nagaya, Masaki; Baskin, Kevin M; Deutsch, Melvin; Ito, Ryotaro; Shneider, Benjamin L; Squires, Robert; Vockley, Jerry; Guha, Chandan; Roy-Chowdhury, Jayanta; Strom, Stephen C; Platt, Jeffrey L; Fox, Ira J. Barriers to the successful treatment of liver disease by hepatocyte transplantation. Journal of hepatology, 2010 Oct; 53 (4):769-74
9. Dawson, Laura A; Guha, Chandan. Hepatocellular carcinoma: radiation therapy. Cancer journal (Sudbury, Mass.), 2008 Mar-Apr; 14 (2):111-6
10. Agoni, Lorenzo; Basu, Indranil; Gupta, Seema; Alfieri, Alan; Gambino, Angela; Goldberg, Gary L; Reddy, E Premkumar; Guha, Chandan. Rigosertib is a more effective radiosensitizer than cisplatin in concurrent chemoradiation treatment of cervical carcinoma, in vitro and in vivo. International journal of radiation oncology, biology, physics, 2014 Apr 1; 88 (5):1180-7