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Forman, Stephen J., M.D., F.A.C.P. Bookmark and Share

Laboratory of Stephen J. Forman, M.D., F.A.C.P.

Advances in surgery, radiation therapy and chemotherapy over the last decade have increased the cure rates of a variety of malignancies.  For patients whose tumors are not eradicated, however, the impediment most frequently encountered is the inability to fully eliminate the minimal residual disease that frequently has acquired resistance to conventional treatment modalities.

A conceptually attractive strategy for targeting minimal residual disease is the manipulation of immunologic effector cells to specifically recognize tumor targets.  Animal models and an increasing number of clinical trials have implicated the T lymphocyte as a pivotal immunologic effector cell in antitumor immunity.  Technologies are now available for identifying T-cell target epitopes expressed by human tumors, isolating T cells for genetic modification to recognize these tumor targets, and then expanding these cells ex vivo to large numbers for reinfusion.  Initial clinical trials for lymphoma, leukemia and malignant glioma employing adoptive transfer of tumor-specific T cells have commenced at City of Hope.
 
T Cell Therapeutics Research Laboratory Members:
 
Christine Brown, Ph.D.
Associate Research Professor
Associate Director of TCTRL
cbrown@coh.org
626-256-HOPE (4673),ext. 63977

Elizabeth Budde, M.D., Ph.D.
Assistant Research Professor
Staff Physician
ebudde@coh.org
626-256-HOPE (4673),ext. 62407
 
Monique Dao, Ph.D.
Assistant Research Professor
mdao@coh.org
626-256-HOPE (4673),ext. 89317
 
Marissa Del Real, Ph.D.
Postdoctoral Fellow
mdelreal@coh.org
626-256-HOPE (4673),ext. 81962
 
Julie Ostberg, Ph.D.
Assistant Research Professor
Scientific Writer
Lab Research Regulatory Coordinator
jostberg@coh.org
626-256-HOPE (4673),ext. 65249
 
Saul Priceman, Ph.D.
Assistant Research Professor
spriceman@coh.org
626-256-HOPE (4673),ext. 64508
 
Sandra Thomas, Ph.D.
Staff Scientist
Scientific Writer
sthomas@coh.org
626-256-HOPE (4673),ext. 64182
 
Xiuli Wang, M.D., Ph.D.
Associate Research Professor
xiuwang@coh.org
626-256-HOPE (4673),ext. 63511
 
Lihong Weng, M.D.
Staff Scientist
lweng@coh.org
626-256-HOPE (4673),ext. 89060
 
Jingying Xu, Ph.D.
Staff Scientist
jixu@coh.org
626-256-HOPE (4673),ext. 63478
 
Brenda Aguilar, B.S.
Senior Research Associate
Animal Studies Supervisor
baguilar@coh.org
626-256-HOPE (4673),ext. 63927
 
Alfonso Brito, M.S.
Research Associate II
abrito@coh.org
626-256-HOPE (4673),ext. 63804
 
Wen Chung Chang, M.S.
Staff Scientist
Molecular Studies Supervisor
wchang@coh.org
626-256-HOPE (4673),ext. 64155

Brenda Chang, B.S.
Research Associate II
bchang@coh.org
626-256-HOPE (4673),ext. 63274
 
Ethan Gerdts, B.S.
Research Associate I
egerdts@coh.org
626-256-HOPE (4673),ext. 62153
 
Martha Gonzalez
Senior Administrative Support
mgonzalez@coh.org
626-256-HOPE (4673),ext. 60201
 
Rochelle Hernandez, B.S.
Research Associate II
rochernandez@coh.org
626-256-HOPE (4673),ext. 81962
 
Anita Kurien, MBS
Regulatory Affairs Specialist I
akurien@coh.org
626-256-HOPE (4673),ext. 60242
 
Araceli Naranjo, B.A.
Staff Scientist
Cell Manufacturing Supervisor
anaranjo@coh.org
626-256-HOPE (4673),ext. 64181
 
Adam Norris, B.S.
Clinical Research Coordinator II
anorris@coh.org
626-256-HOPE (4673),ext. 62312
 
Alina Oancea, M.D., M.S.
Research Associate II
aoancea@coh.org
626-256-HOPE (4673),ext. 64533
 
Anthony Park, M.S.
Intern
apark@coh.org
626-256-HOPE (4673),ext. 62153
 
Alexandra Pike
Trainee
apike@coh.org
626-256-HOPE (4673),ext. 62153
 
Lauren Quezada, M.S.
Research Associate II
lquezada@coh.org
626-256-HOPE (4673),ext. 64533
 
Aniee Sarkissian, M.S.
Research Associate II
asarkissian@coh.org
626-256-HOPE (4673),ext. 63927
 
Jennifer Simpson, B.A.
Clinical Research Coordinator III
jsimpson@coh.org
626-256-HOPE (4673),ext. 65087
 
Renate Starr, M.S.
Senior Research Associate
TCTRL Lab Manager
rstarr@coh.org
626-256-HOPE (4673),ext. 63274
 
Ellie Taus, B.S.
Research Associate I
etaus@coh.org
626-256-HOPE (4673),ext. 81937
 
Dileshni Tilakawardane
Research Associate I
dtilakawardane@coh.org
626-256-HOPE (4673), ext. 82153
 
Ryan Urak, M.S.
Research Associate II
rurak@coh.org
626-256-HOPE (4673),ext. 81937
 
Leonor Velasco
Research Lab Technician
lvelasco@coh.org
626-256-HOPE (4673),ext. 64184
 
Jamie Wagner, B.A.
Regulatory Affairs Specialist III
Clinical Research Regulatory Coordinator
jwagner@coh.org
626-256-HOPE (4673),ext. 60056
 
Laurelin Wolfenden, B.S.
Research Associate I
lwolfenden@coh.org
626-256-HOPE (4673),ext. 64533

Winnie Wong, B.S.
Senior Research Associate
wiwong@coh.org
626-256-HOPE (4673),ext. 81937
 
Sarah Wright, B.S.
Research Associate I
sawright@coh.org
626-256-HOPE (4673),ext. 63804
 
Xin (Cindy) Yang
Research Associate I
xyang@coh.org
626-256-HOPE (4673), ext. 68969

Stephen J. Forman, M.D., F.A.C.P. Research

Adoptive Immunotherapy
Advances in surgery, radiation therapy and chemotherapy over the last decade have increased the cure rates of a variety of malignancies. For patients whose tumors are not eradicated, however, the impediment most frequently encountered is the inability to fully eliminate the minimal residual disease that often has acquired resistance to conventional treatment modalities. An attractive strategy for targeting minimal residual disease is the manipulation of immunologic effector cells to specifically recognize tumor targets. Animal models and an increasing number of clinical trials have implicated the T lymphocyte as a pivotal immunologic effector cell in anti-tumor immunity. This has led to our overall interest in using adoptive immunotherapy of T-cells to target cancer, specifically leukemia/lymphoma, brain tumors and neuroblastoma. Areas of focus in our research program are outlined below.
 
Glioma tumor cells are killed by therapeutic T-cells
Scanning of zetakine redirected cytolytic T-cell lysis of a glioma tumor cell.
 
Genetic Modification of T-cells for Redirected Tumor Recognition
Technologies are now available for identifying immunogenic T-cell target epitopes expressed by human tumors, isolating antigen-specific T-cells and expanding them ex vivo to large numbers for reinfusion. However, to overcome the difficulties of isolating tumor-reactive T-cells from cancer patients, we have developed technology to take T-cells from a cancer patient and reprogram them to target a patient’s cancer through genetic engineering strategies using DNA electroporation and/or lentiviral transduction. Previous studies by our laboratory have provided proof of principle that CTL can be engineered to specifically target lymphoma, neuroblastoma, and glioma tumors via expression of tumor-specific chimeric immunoreceptors resulting in MHC-independent killing of target tumor cells (Cooper et al, Blood 2003; Park et al, Mol Therapy 2007; Kahlon et al, Cancer Res 2004). More recently, we have completed pre-clinical studies of cytotoxic T-cells (CTLs) genetically modified to express an IL13-zetakine chimeric immunoreceptor to target cell-surface IL13Rα2 on medulloblastoma/primitive neuroectodermal tumors, the most common type of brain tumor in children (Stastny et al, J Ped Hematol Oncol 2007). Overall, we are currently involved in studying the potential clinical utility of adoptively transferring T-cells that have been genetically redirected to recognize CD19 (on leukemia and lymphoma); IL13Ra2 (on glioblastoma and medulloblastoma); L1-CAM (on neuroblastoma, lung cancer, and renal cell carcinoma); HER2 (on breast cancer, brain metastases and medulloblastoma); or alpha-3 integrin (on medulloblastoma).
 
 
Murine Xenograft ModelsSurgical suite
To monitor the therapeutic objectives of adoptive T-cell transfer before entering the clinical setting, our lab has developed multiple murine xenograft models. For example, we are now routinely performing stereotactic surgeries in mice for the intracranial injection of human brain tumors to mimic the situation of our patients. In addition, we have also developed lymphoma, neuroblastoma, and medulloblastoma murine xenograft models. Bioluminescent strategies have also been developed by our group for the in vivo imaging of both T-cells and tumors. Our utilization of the firefly and renilla luciferase genes (ffLuc and rLuc, respectively) along with the Xenogen system for serial imaging of anesthetized mice has been critically important for evaluating our animal studies. Specifically, these animal model systems are being used for studying the efficacy of immunotherapy, T-cell trafficking from tail vein injections, contralateral homing of T-cells to tumors within the parenchyma of the brain, and studies of T-cell persistence and proliferation.
 
Trafficking of Adoptively Transferred T-cells
To exert a therapeutic effect, adoptively transferred tumor-specific cytotoxic T-cells (CTLs) must traffic to sites of tumor burden, exit the circulation, and infiltrate the tumor microenvironment. T-cells are able to respond to migration directing chemicals, called chemokines, that are produced by tumor cells. Thus our group has begun to examine the ability of adoptively transferred human CTLs to traffic to tumors. Using a combination of in vivo tumor tropism studies, and in vitro biophotonic chemotaxis assays, we observed that tumors that produce CCL2/MCP1 (>10ng/ml), such as cell lines derived from glioma and medulloblastoma, efficiently chemoattract ex vivo expanded primary human T-cells. These studies suggest that the capacity of adoptively transferred T-cells to home to tumors may be influenced in part by the species and amounts of tumor-derived chemokines, in particular MCP-1 (Brown et al, J Immunol 2007).
 
Targeting Tumor Progenit or Cells with Genetically Engineered Effector T-Cells
Recent hypotheses that tumors arise from cancer stem cells which appear to be resistant to radiation treatment and chemotherapy have also led us to begin to isolate and expand stem cells from human glioma to assess the vulnerability of these cells to T-cell mediated killing in our adoptive immunotherapy models. Our initial studies demonstrate that chimeric immunoreceptor redirected IL13Rα2-specific CTL, currently being evaluated in an FDA-approved pilot Phase I trial for the treatment of recurrent/refractory malignant glioma, can kill cancer stem/progenitor cells in vitro, and reduce engrafted potential of the glioma stem/progenitor population in an orthotopic murine tumor model. Current models now predict that curative therapies for many cancers might require the elimination of the stem/progenitor population, and these studies lay the foundation for an immunotherapy approach to achieve this goal.
 
Development of Strategies to Optimize T-cell Anti-Tumor Activity in Vivo
Our group has also begun to investigate the expression of additional gene products in T-cells that may serve to overcome constraints on T-cell effector function and survival in vivo. For example, we are currently examining the efficacy of providing co-stimulatory signaling to T-cells through integration of costimulatory signaling domains within a tumor targeting chimeric antigen receptor.  Our recent studies in this area demonstrate that integrating costimulation with activation signaling events is important for fully activating CD4+ anti-tumor effector cells, resulting in sustained function in the tumor microenvironment.
 
Another strategy we are currently examining is the utility of genetically modifying T-cells which have first been selected for specificity to viruses such as CMV or EBV, which would allow for endogenous stimulation of these T-cells upon their transfer to patients infected with these viruses that are frequently reactivated in infected hosts. We would also predict that such a combinatorial bispecific T-cell strategy would permit the selective isolation of virus specific memory T-cells as recipients of chimeric antigen receptor genes for improved in vivo persistence following adoptive transfer. In fact, studies on the unique engraftment potential of memory T-cells are also being carried out in primates in collaboration with Dr. Berger at the Fred Hutchison Cancer Research Center in Seattle, WA. Because tumors can avoid immune-mediated elimination by production of immunosuppressive cytokines (e.g., TGF-b), our group is also evaluating strategies by which T-cells may be rendered resistant to such immunosupression. One project is the development of interference RNA sequences that could decrease this susceptibility of T-cells to tumor-mediated suppression. In collaboration with Sangamo Biosciences in Richmond, CA, we are also interested in studying the effects of genetically blocking glucocorticoid sensitivity of the tumor specific T-cells because post-operative brain cancer patients are routinely treated with immunosuppressive steroids (i.e., glucocorticoids) to reduce clinical symptoms of edema.
 
Lastly, another group of projects underway in the lab are examining ways of generating gene products that influence the expression of cytokines such as IL-2 and IL-7 which help promote the survival of T-cells and are critical for generating T-cell memory responses. A new collaboration with Dr. Smolke in the Chemical Engineering Department at CalTech involves the development of RNA regulating systems that are inducible by drugs such as tetracycline to control the expression of cytokines in T-cells which will promote their proliferation and survival.
 
Overall, the recent progress and current directions of Dr. Forman’s research group have generated much enthusiasm and support at City of Hope. The laboratory and office space in the Arnold and Mabel Beckman Center for Cancer Immunotherapeutics & Tumor Immunology is located in the heart of City of Hope. This state-of-the-art center is dedicated to immunotherapy and facilitates collaboration between lab researchers and clinicians, and rapidly moves scientific discoveries from the lab to patients.
 
 

Forman, Stephen J., M.D., F.A.C.P.

Laboratory of Stephen J. Forman, M.D., F.A.C.P.

Advances in surgery, radiation therapy and chemotherapy over the last decade have increased the cure rates of a variety of malignancies.  For patients whose tumors are not eradicated, however, the impediment most frequently encountered is the inability to fully eliminate the minimal residual disease that frequently has acquired resistance to conventional treatment modalities.

A conceptually attractive strategy for targeting minimal residual disease is the manipulation of immunologic effector cells to specifically recognize tumor targets.  Animal models and an increasing number of clinical trials have implicated the T lymphocyte as a pivotal immunologic effector cell in antitumor immunity.  Technologies are now available for identifying T-cell target epitopes expressed by human tumors, isolating T cells for genetic modification to recognize these tumor targets, and then expanding these cells ex vivo to large numbers for reinfusion.  Initial clinical trials for lymphoma, leukemia and malignant glioma employing adoptive transfer of tumor-specific T cells have commenced at City of Hope.
 
T Cell Therapeutics Research Laboratory Members:
 
Christine Brown, Ph.D.
Associate Research Professor
Associate Director of TCTRL
cbrown@coh.org
626-256-HOPE (4673),ext. 63977

Elizabeth Budde, M.D., Ph.D.
Assistant Research Professor
Staff Physician
ebudde@coh.org
626-256-HOPE (4673),ext. 62407
 
Monique Dao, Ph.D.
Assistant Research Professor
mdao@coh.org
626-256-HOPE (4673),ext. 89317
 
Marissa Del Real, Ph.D.
Postdoctoral Fellow
mdelreal@coh.org
626-256-HOPE (4673),ext. 81962
 
Julie Ostberg, Ph.D.
Assistant Research Professor
Scientific Writer
Lab Research Regulatory Coordinator
jostberg@coh.org
626-256-HOPE (4673),ext. 65249
 
Saul Priceman, Ph.D.
Assistant Research Professor
spriceman@coh.org
626-256-HOPE (4673),ext. 64508
 
Sandra Thomas, Ph.D.
Staff Scientist
Scientific Writer
sthomas@coh.org
626-256-HOPE (4673),ext. 64182
 
Xiuli Wang, M.D., Ph.D.
Associate Research Professor
xiuwang@coh.org
626-256-HOPE (4673),ext. 63511
 
Lihong Weng, M.D.
Staff Scientist
lweng@coh.org
626-256-HOPE (4673),ext. 89060
 
Jingying Xu, Ph.D.
Staff Scientist
jixu@coh.org
626-256-HOPE (4673),ext. 63478
 
Brenda Aguilar, B.S.
Senior Research Associate
Animal Studies Supervisor
baguilar@coh.org
626-256-HOPE (4673),ext. 63927
 
Alfonso Brito, M.S.
Research Associate II
abrito@coh.org
626-256-HOPE (4673),ext. 63804
 
Wen Chung Chang, M.S.
Staff Scientist
Molecular Studies Supervisor
wchang@coh.org
626-256-HOPE (4673),ext. 64155

Brenda Chang, B.S.
Research Associate II
bchang@coh.org
626-256-HOPE (4673),ext. 63274
 
Ethan Gerdts, B.S.
Research Associate I
egerdts@coh.org
626-256-HOPE (4673),ext. 62153
 
Martha Gonzalez
Senior Administrative Support
mgonzalez@coh.org
626-256-HOPE (4673),ext. 60201
 
Rochelle Hernandez, B.S.
Research Associate II
rochernandez@coh.org
626-256-HOPE (4673),ext. 81962
 
Anita Kurien, MBS
Regulatory Affairs Specialist I
akurien@coh.org
626-256-HOPE (4673),ext. 60242
 
Araceli Naranjo, B.A.
Staff Scientist
Cell Manufacturing Supervisor
anaranjo@coh.org
626-256-HOPE (4673),ext. 64181
 
Adam Norris, B.S.
Clinical Research Coordinator II
anorris@coh.org
626-256-HOPE (4673),ext. 62312
 
Alina Oancea, M.D., M.S.
Research Associate II
aoancea@coh.org
626-256-HOPE (4673),ext. 64533
 
Anthony Park, M.S.
Intern
apark@coh.org
626-256-HOPE (4673),ext. 62153
 
Alexandra Pike
Trainee
apike@coh.org
626-256-HOPE (4673),ext. 62153
 
Lauren Quezada, M.S.
Research Associate II
lquezada@coh.org
626-256-HOPE (4673),ext. 64533
 
Aniee Sarkissian, M.S.
Research Associate II
asarkissian@coh.org
626-256-HOPE (4673),ext. 63927
 
Jennifer Simpson, B.A.
Clinical Research Coordinator III
jsimpson@coh.org
626-256-HOPE (4673),ext. 65087
 
Renate Starr, M.S.
Senior Research Associate
TCTRL Lab Manager
rstarr@coh.org
626-256-HOPE (4673),ext. 63274
 
Ellie Taus, B.S.
Research Associate I
etaus@coh.org
626-256-HOPE (4673),ext. 81937
 
Dileshni Tilakawardane
Research Associate I
dtilakawardane@coh.org
626-256-HOPE (4673), ext. 82153
 
Ryan Urak, M.S.
Research Associate II
rurak@coh.org
626-256-HOPE (4673),ext. 81937
 
Leonor Velasco
Research Lab Technician
lvelasco@coh.org
626-256-HOPE (4673),ext. 64184
 
Jamie Wagner, B.A.
Regulatory Affairs Specialist III
Clinical Research Regulatory Coordinator
jwagner@coh.org
626-256-HOPE (4673),ext. 60056
 
Laurelin Wolfenden, B.S.
Research Associate I
lwolfenden@coh.org
626-256-HOPE (4673),ext. 64533

Winnie Wong, B.S.
Senior Research Associate
wiwong@coh.org
626-256-HOPE (4673),ext. 81937
 
Sarah Wright, B.S.
Research Associate I
sawright@coh.org
626-256-HOPE (4673),ext. 63804
 
Xin (Cindy) Yang
Research Associate I
xyang@coh.org
626-256-HOPE (4673), ext. 68969

Research

Stephen J. Forman, M.D., F.A.C.P. Research

Adoptive Immunotherapy
Advances in surgery, radiation therapy and chemotherapy over the last decade have increased the cure rates of a variety of malignancies. For patients whose tumors are not eradicated, however, the impediment most frequently encountered is the inability to fully eliminate the minimal residual disease that often has acquired resistance to conventional treatment modalities. An attractive strategy for targeting minimal residual disease is the manipulation of immunologic effector cells to specifically recognize tumor targets. Animal models and an increasing number of clinical trials have implicated the T lymphocyte as a pivotal immunologic effector cell in anti-tumor immunity. This has led to our overall interest in using adoptive immunotherapy of T-cells to target cancer, specifically leukemia/lymphoma, brain tumors and neuroblastoma. Areas of focus in our research program are outlined below.
 
Glioma tumor cells are killed by therapeutic T-cells
Scanning of zetakine redirected cytolytic T-cell lysis of a glioma tumor cell.
 
Genetic Modification of T-cells for Redirected Tumor Recognition
Technologies are now available for identifying immunogenic T-cell target epitopes expressed by human tumors, isolating antigen-specific T-cells and expanding them ex vivo to large numbers for reinfusion. However, to overcome the difficulties of isolating tumor-reactive T-cells from cancer patients, we have developed technology to take T-cells from a cancer patient and reprogram them to target a patient’s cancer through genetic engineering strategies using DNA electroporation and/or lentiviral transduction. Previous studies by our laboratory have provided proof of principle that CTL can be engineered to specifically target lymphoma, neuroblastoma, and glioma tumors via expression of tumor-specific chimeric immunoreceptors resulting in MHC-independent killing of target tumor cells (Cooper et al, Blood 2003; Park et al, Mol Therapy 2007; Kahlon et al, Cancer Res 2004). More recently, we have completed pre-clinical studies of cytotoxic T-cells (CTLs) genetically modified to express an IL13-zetakine chimeric immunoreceptor to target cell-surface IL13Rα2 on medulloblastoma/primitive neuroectodermal tumors, the most common type of brain tumor in children (Stastny et al, J Ped Hematol Oncol 2007). Overall, we are currently involved in studying the potential clinical utility of adoptively transferring T-cells that have been genetically redirected to recognize CD19 (on leukemia and lymphoma); IL13Ra2 (on glioblastoma and medulloblastoma); L1-CAM (on neuroblastoma, lung cancer, and renal cell carcinoma); HER2 (on breast cancer, brain metastases and medulloblastoma); or alpha-3 integrin (on medulloblastoma).
 
 
Murine Xenograft ModelsSurgical suite
To monitor the therapeutic objectives of adoptive T-cell transfer before entering the clinical setting, our lab has developed multiple murine xenograft models. For example, we are now routinely performing stereotactic surgeries in mice for the intracranial injection of human brain tumors to mimic the situation of our patients. In addition, we have also developed lymphoma, neuroblastoma, and medulloblastoma murine xenograft models. Bioluminescent strategies have also been developed by our group for the in vivo imaging of both T-cells and tumors. Our utilization of the firefly and renilla luciferase genes (ffLuc and rLuc, respectively) along with the Xenogen system for serial imaging of anesthetized mice has been critically important for evaluating our animal studies. Specifically, these animal model systems are being used for studying the efficacy of immunotherapy, T-cell trafficking from tail vein injections, contralateral homing of T-cells to tumors within the parenchyma of the brain, and studies of T-cell persistence and proliferation.
 
Trafficking of Adoptively Transferred T-cells
To exert a therapeutic effect, adoptively transferred tumor-specific cytotoxic T-cells (CTLs) must traffic to sites of tumor burden, exit the circulation, and infiltrate the tumor microenvironment. T-cells are able to respond to migration directing chemicals, called chemokines, that are produced by tumor cells. Thus our group has begun to examine the ability of adoptively transferred human CTLs to traffic to tumors. Using a combination of in vivo tumor tropism studies, and in vitro biophotonic chemotaxis assays, we observed that tumors that produce CCL2/MCP1 (>10ng/ml), such as cell lines derived from glioma and medulloblastoma, efficiently chemoattract ex vivo expanded primary human T-cells. These studies suggest that the capacity of adoptively transferred T-cells to home to tumors may be influenced in part by the species and amounts of tumor-derived chemokines, in particular MCP-1 (Brown et al, J Immunol 2007).
 
Targeting Tumor Progenit or Cells with Genetically Engineered Effector T-Cells
Recent hypotheses that tumors arise from cancer stem cells which appear to be resistant to radiation treatment and chemotherapy have also led us to begin to isolate and expand stem cells from human glioma to assess the vulnerability of these cells to T-cell mediated killing in our adoptive immunotherapy models. Our initial studies demonstrate that chimeric immunoreceptor redirected IL13Rα2-specific CTL, currently being evaluated in an FDA-approved pilot Phase I trial for the treatment of recurrent/refractory malignant glioma, can kill cancer stem/progenitor cells in vitro, and reduce engrafted potential of the glioma stem/progenitor population in an orthotopic murine tumor model. Current models now predict that curative therapies for many cancers might require the elimination of the stem/progenitor population, and these studies lay the foundation for an immunotherapy approach to achieve this goal.
 
Development of Strategies to Optimize T-cell Anti-Tumor Activity in Vivo
Our group has also begun to investigate the expression of additional gene products in T-cells that may serve to overcome constraints on T-cell effector function and survival in vivo. For example, we are currently examining the efficacy of providing co-stimulatory signaling to T-cells through integration of costimulatory signaling domains within a tumor targeting chimeric antigen receptor.  Our recent studies in this area demonstrate that integrating costimulation with activation signaling events is important for fully activating CD4+ anti-tumor effector cells, resulting in sustained function in the tumor microenvironment.
 
Another strategy we are currently examining is the utility of genetically modifying T-cells which have first been selected for specificity to viruses such as CMV or EBV, which would allow for endogenous stimulation of these T-cells upon their transfer to patients infected with these viruses that are frequently reactivated in infected hosts. We would also predict that such a combinatorial bispecific T-cell strategy would permit the selective isolation of virus specific memory T-cells as recipients of chimeric antigen receptor genes for improved in vivo persistence following adoptive transfer. In fact, studies on the unique engraftment potential of memory T-cells are also being carried out in primates in collaboration with Dr. Berger at the Fred Hutchison Cancer Research Center in Seattle, WA. Because tumors can avoid immune-mediated elimination by production of immunosuppressive cytokines (e.g., TGF-b), our group is also evaluating strategies by which T-cells may be rendered resistant to such immunosupression. One project is the development of interference RNA sequences that could decrease this susceptibility of T-cells to tumor-mediated suppression. In collaboration with Sangamo Biosciences in Richmond, CA, we are also interested in studying the effects of genetically blocking glucocorticoid sensitivity of the tumor specific T-cells because post-operative brain cancer patients are routinely treated with immunosuppressive steroids (i.e., glucocorticoids) to reduce clinical symptoms of edema.
 
Lastly, another group of projects underway in the lab are examining ways of generating gene products that influence the expression of cytokines such as IL-2 and IL-7 which help promote the survival of T-cells and are critical for generating T-cell memory responses. A new collaboration with Dr. Smolke in the Chemical Engineering Department at CalTech involves the development of RNA regulating systems that are inducible by drugs such as tetracycline to control the expression of cytokines in T-cells which will promote their proliferation and survival.
 
Overall, the recent progress and current directions of Dr. Forman’s research group have generated much enthusiasm and support at City of Hope. The laboratory and office space in the Arnold and Mabel Beckman Center for Cancer Immunotherapeutics & Tumor Immunology is located in the heart of City of Hope. This state-of-the-art center is dedicated to immunotherapy and facilitates collaboration between lab researchers and clinicians, and rapidly moves scientific discoveries from the lab to patients.
 
 
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Our research laboratories are led by the best and brightest minds in scientific research.
 

Beckman Research Institute of City of Hope is internationally  recognized for its innovative biomedical research.
City of Hope is one of only 41 Comprehensive Cancer Centers in the country, the highest designation awarded by the National Cancer Institute to institutions that lead the way in cancer research, treatment, prevention and professional education.

Learn more about
City of Hope's institutional distinctions, breakthrough innovations and collaborations.
 
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By giving to City of Hope, you support breakthrough discoveries in laboratory research that translate into lifesaving treatments for patients with cancer and other serious diseases.
 
 
 
 


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  • Although most cancer occurs in older adults, the bulk of cancer research doesn’t focus on this vulnerable and fast-growing population. City of Hope and its Cancer and Aging Research Team aim to change that, and they’re getting a significant boost from Professional Practice Leader Peggy Burhenn, R.N....
  • Liz Graef-Larcher’s first brain tumor was discovered by accident six years ago. The then-48-year-old with a long history of sinus problems and headaches had been sent for an MRI, and the scan found a lesion in her brain called a meningioma – a tumor that arises in the meninges, the layers of tissue that cover a...
  • The colon and rectum are parts of the body’s gastrointestinal system, also called the digestive tract. After food is digested in the stomach and nutrients are absorbed in the small intestine, the remaining material moves down into the lower large intestine (colon) where water and nutrients are absorbed. The low...
  • If there is one truism about hospital stays it is that patients want to get out. For many, however, the joy of being discharged is tempered by the unexpected challenges that recovery in a new setting may pose. Even with professional help, the quality of care and treatment that patients receive at City of Hope [...
  • Jana Portnow, M.D., associate director of the Brain Tumor Program at City of Hope, didn’t expect to specialize in treating brain tumors. But, early in her career, she undertook a year of research on pain management and palliative care and, in that program, got to know many patients with brain tumors. After that...
  • Ask any patient: Nurses are as pivotal in their care as doctors. They answer the call of a patient in the middle of the night, they hold the patient’s hand as he or she takes on yet another round of treatment and, in the best-case scenario, they wave goodbye as the patient leaves the hospital, […]
  • Many oncologists, not to mention their patients, might think that there’s no place for mathematical analysis in the treatment of cancer. They might think that all treatment decisions are based on unique factors affecting individual patients, with no connection to other patients and their treatment regimen...
  • Within three days in 2007, Stephanie Hosford, then 37, learned that she was pregnant with her long-awaited second child – and that she had triple-negative breast cancer. Soon afterward, Hosford discovered that she and her husband, Grant, had been approved to adopt a little girl from China.  After encountering m...