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Laboratory of Tumor Immunology and Biology

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Research

I. LABORATORY OVERVIEW
II. STAFF OVERVIEW
III. SUMMARY OF RESEARCH ACTIVITIES/RECENT ACCOMPLISHMENTS
IV. CLINICAL RESEARCH PROTOCOLS AT THE CENTER FOR CANCER RESEARCH, NIH
V. STAFF SCIENTIST POSITION AVAILABLE

For contact information on clinical trials, scroll down. For further information on clinical trials, see "Links".

I. LABORATORY OVERVIEW

The Laboratory of Tumor Immunology and Biology conducts translational research in the areas of tumor immunology, immunotherapy, mechanisms of tumor cell-immune cell interactions, and immune mechanisms. The laboratory functions as an integrated translational research program with the goal of designing and developing new immunotherapies and immunologic strategies for cancer treatment and prevention. Ongoing studies involve (1) the analysis of basic immunologic mechanisms and principles, (2) the design and development of novel recombinant vaccines, (3) analysis of tumor cell-immune cell interactions, (4) the discovery of antigenic determinants expressed in human cancers as vaccine or monoclonal antibody targets, (5) the development of new animal models that can be employed in preclinical studies to most reflect human vaccine trials, (6) cytokine biology as it integrates with cancer immunotherapy, (7) the development of clinical grade vaccines and immunostimulants for use in immunotherapy trials for a range of human cancers, (8) collaborative clinical trials involving recombinant vaccines and vaccine strategies in patients with a range of human cancers, and (9) the development of new immunoassays to define immune responses to vaccines from patients enrolled in vaccine trials.

II. STAFF OVERVIEW
Recombinant Vaccine Group
James W. Hodge, Ph.D., MBA, Head
Focuses research on the design and development of novel recombinant vaccines and on innovative preclinical studies to define how vaccines can optimally be employed with standard of care therapies and other new experimental therapies. These hypothesis-driven preclinical studies have formed the rationale for the approval of numerous clinical trials both at NCI and at Extramural sites.

Cytokine Group
Jack W. Greiner, Ph.D., Head
Focuses research on the use of recombinant protein and vector-mediated cytokines to obtain optimal vaccine-mediated immunotherapeutic responses and on the development of animal models of spontaneously rising tumors to analyze the use of vaccines and combination therapies in the prevention and/or treatment of carcinomas.

Cellular Immunology Group
Kwong (Al) Tsang, Ph.D., Head
Focuses research on the identification of T-cell epitopes and enhancer epitopes of tumor-associated antigens, many of which have now been incorporated into vaccines in clinical studies. Research also involves the development and use of novel immunoassays to define immune responses of patients prior to and post multiple vaccinations. These studies are vital to an understanding of the consequences of the use of vaccines in clinical trials alone and in combination therapies.

Molecular Immunology Group
Helen Sabzevari, Ph.D., Head
Focuses research on the mechanisms involved in the activation/regulation of naive vs memory T cells and those mechanisms involved in the control of immunologic tolerance to self antigens.

Immunoregulation Group
Claudia Palena, Ph.D., Head
Focuses research on those factors that will enhance the activation of
human T cells, with emphasis on the use of enhanced costimulation in human antigen-presenting cells. Research also involves collaborative studies on the identification of new targets for vaccine-mediated immunotherapy.

Immunotherapeutics Group
Jeffrey Schlom, Ph.D., Head
Focuses research on those factors that will enhance the activity of murine and human memory T cells. These studies have important implications in clinical trial design.

CLINICAL GROUPS

Clinical Research Group
Philip Arlen, M.D., Director
The Clinical Research Group designs and carries out clinical studies focusing on the integration of cancer vaccines with standard of care therapies such as hormone therapy and chemotherapy.

Clinical Trials Group
James Gulley, M.D., Ph.D., Director
The Clinical Trials Group designs and carries out clinical studies focusing on the use of cancer vaccines with other experimental therapies and novel strategies.


III. RESEARCH ACTIVITIES/RECENT ACCOMPLISHMENTS

A. Enhancement of Immune Responses and Anti-Tumor Activity: Experimental Studies
[] The design and development of recombinant vectors containing transgenes for a tumor-associated antigen (TAA) and three T-cell costimulatory molecules (B7.1, ICAM-1, LFA-3, designated TRICOM) and their optimization in preclinical studies for use to enhance T-cell responses and anti-tumor activity against established tumors. These studies have led to several clinical trials for a range of human carcinomas.
[] The demonstration for the first time that the use of costimulation in vector-based vaccines, and the use of GM-CSF, and/or anti-CTLA-4 MAb greatly enhance the functional avidity of T cells generated.
[] The demonstration that murine and human T cells actually acquire MHC/costimulatory molecule complexes from APC and the demonstration for the first time of the functional relevance of this acquisition in the expansion and regulation of naive vs memory T cells.
[] The demonstration that low-dose cyclophosphamide not only alters the number of TREGS, but also alters their function.
[] The first comparison of systemic (s.c.) vs intratumoral (i.t.) vaccinations and the demonstration that optimal anti-tumor activity can be achieved by vaccine priming s.c. and boosting i.t. These findings have now been translated to clinical studies.
[] The demonstration that introducing more signal 1 (antigen) to tumor via intratumoral vaccination can enhance anti-tumor T-cell responses via enhancing the number of immunologic synapses and T-cell signaling.
[] The demonstration of the importance of antigen cascade in therapeutic anti-tumor responses to vaccine, where the induction of T cells specific for antigens distinct from those in the vaccine are shown to play an extremely important role in anti-tumor responses. These studies have important implications in the analyses of immune responses in vaccine clinical trials, and in the selection of new targets for vaccine-mediated therapy.
[] The demonstration in animal models for the first time that (i) that tumor regression in a CTL adoptive transfer lung metastasis model occurred via Fas/FasL interactions, (ii) that tumor eradication by Fas/FasL interactions also served as selective pressure for the emergence of Fas-resistant/ refractory, aggressive tumor escape variants, and (iii) that the expression of ICSBP in both human and mouse solid tumor cell lines correlated with susceptibility to Fas-mediated death, and inversely correlated with malignant phenotype. Differential expression of Fas and ICSBP may thus be important factors of tumor progression, with potential clinical value.

B. Vaccine Combination Therapies: Experimental Models
[] The demonstration that external beam irradiation of tumor, or the use of certain chemotherapeutic agents and/or their combination, can alter the phenotype of tumor cells and render them more susceptible to vaccine-mediated T-cell killing. These findings have now been translated to clinical studies.
[] The demonstration that multi-modal therapy (vaccine, external beam irradiation of tumor, and control of TREG cells) can be combined to further enhance antigen-specific T-cell responses, and anti-tumor activity.
[] The development of a model for human familial adenomatous polyposis (FAP) to demonstrate that CEA-TRICOM vaccines plus COX-2 inhibitor (Celebrex) can eliminate spontaneously arising colon tumors expressing CEA.

C. Activation of Human T Cells to Tumor Antigens
[] The identification and characterization of novel enhancer agonist CTL epitopes for PSA, CEA, and MUC-1, which have now been incorporated into vaccines in clinical trials.
[] The first studies to employ gene array and RT-PCR to identify those genes in human T cells that are regulated as a consequence of stimulation by a defined epitope vs its agonist.
[] The development of the first viral vectors faithfully expressing transgenes for two TAAs and three human T-cell costimulatory molecules.
[] Collaborative studies with four gene discovery groups, which has led to the identification of several novel CTL and agonist epitopes of TAAs as new vaccine targets.
[] The first studies to demonstrate a method of inducing higher avidity human CTLs.
[] The demonstration that the use of recombinant TRICOM vectors to infect human B cells can greatly enhance their ability to activate human T cells, thus providing a potential alternative to the costly and labor-intensive use of dendritic cells for vaccines.
[] The demonstration that TRICOM vectors can infect human chronic lymphocytic leukemia (CLL) cells and render them capable of activating T cells with the ability to lyse autologous CLL cells.

D. Immunotherapy: Clinical Studies
[] The development and FDA approval for clinical studies of eight new recombinant vaccines, one agonist peptide vaccine, and two radionuclide-conjugated recombinant Igs. These recombinant vector-based vaccines were developed in a science-based progressive manner to contain transgenes for one, then three costimulatory molecules along with one then two transgenes for TAAs.
[] The completion of three clinical studies in patients with different stages of prostate cancer demonstrated that vaccine (recombinant vaccinia (rV)-PSA + rV-B7.1 followed by recombinant fowlpox (rF)-PSA) could be safely employed with external beam irradiation of tumor, second-line hormone therapy, and Taxotere, and provided preliminary evidence of prolongation of time to disease progression, and antigen cascade post-vaccination.
[] The completion of the first clinical trials with rV-, rF-PSA-TRICOM vaccines in patients with metastatic prostate cancer, providing evidence of clinical activity that correlated with the generation of PSA-specific T-cell responses. These trials have led to planned NCI-sponsored randomized multicenter Phase II/III trials.
[] The completion of the first Phase I/II collaborative clinical trial employing rV-, rF-CEA-TRICOM vaccines, demonstrating the advantage of a diversified prime and boost schema with the inclusion of GM-CSF. Correlations were seen between CEA-specific T-cell responses and survival; this trial also provided evidence for the need for continued boosting with vaccine to maintain disease stabilization.
[] The completion of the first NCI Phase I/II clinical trials employing rV-, rF-PANVAC (CEA-MUC-1-TRICOM) vaccines plus GM-CSF, providing evidence of clinical activity that has led to subsequent clinical trials.
[] The establishment of a network of collaborative clinical trials with several Branches within the CCR/NCI, at 10 Extramural Cancer Centers and Cooperative Groups to provide a scientific-based programmatic approach to cancer vaccine clinical trial development.

IV. CLINICAL RESEARCH PROTOCOLS AT THE CENTER FOR CANCER RESEARCH, NIH

Clinical Research Group: P. Arlen, M.D., is P.I. or Protocol Chairman

IN PROGRESS:

A Randomized Pilot Phase II Study of Docetaxel Alone or in Combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in Patients with Metastatic Breast Cancer (NCI 05C-0229)
P.I.: Philip M. Arlen, M.D., LTIB, MOB; Associate Investigators: James L. Gulley, M.D., Ph.D., LTIB, MOB; Sandra Swain, M.D., MOB, NCI

A Phase I-II Study of Tumor Vaccine Following Chemotherapy in Patients with Previously Untreated Metastatic Breast Cancer: Vaccine-Induced Bias of T-Cell Repertoire Reconstitution after T-Cell Re-Infusion (NCI 03-C-0040)
P.I.: Claude Sportes, M.D., MOB, NCI; Associate Investigators: Philip M. Arlen, M.D., LTIB, MOB; James L. Gulley, M.D., Ph.D., LTIB, MOB

A Randomized Phase II Trial Combining Vaccine Therapy with PROSTVAC/TRICOM and Flutamide, vs Flutamide Alone in Patients with Androgen Insensitive, Non Metastatic (D0.5) Prostate Cancer (NCI-07-C-0107)
P.I.: Philip M. Arlen, M.D., LTIB, MOB; Associate Investigators: James L. Gulley, M.D., Ph.D., LTIB, MOB; William Dahut, M.D., MOB, NCI

IN REVIEW:

Evaluation of PANVAC in Allogeneic Cellular Immunotherapy for the Treatment of Metastatic Breast Cancer (CTEP # 7464)
Protocol Chair: Philip M. Arlen, M.D., LTIB, MOB; Co-P.I.: Michael Bishop, M.D., Experimental Transplantation and Immunology Branch and MOB, NCI; Associate Investigator: James L. Gulley, M.D., Ph.D., LTIB, MOB

RECENTLY COMPLETED:

A Randomized Phase II Study of Either Immunotherapy with a Regimen of Recombinant Pox Viruses That Express PSA/B7.1 Plus Adjuvant GM-CSF and IL-2 or Hormone Therapy with Nilutamide in Patients with Hormone Refractory Prostate Cancer and No Radiographic Evidence of Disease (NCI 00-C-0137)
P.I.: Philip M. Arlen, M.D., LTIB, MOB; Associate Investigators: James L. Gulley, M.D., Ph.D., LTIB, MOB; William Dahut, M.D., MOB, NCI

A Pilot Trial of Pox Vector PSA Vaccine with Concurrent Docetaxel versus Pox Vector PSA Vaccine Followed by Docetaxel in Metastatic Androgen Independent Prostate Cancer (NCI 02-C-0218)
Protocol Chair: Philip M. Arlen, M.D., LTIB, MOB; P.I.: William Dahut, M.D., MOB, NCI; Associate Investigator: James L. Gulley, M.D., Ph.D., LTIB, MOB

A Phase I Pilot Study of Sequential Vaccinations with rFowlpox-PSA (L155) TRICOM (PROSTVAC-F/TRICOM) Alone or in Combination with rVaccinia-PSA (L155) TRICOM (PROSTVAC-V/TRICOM) and the Role of GM-CSF, in Patients with Prostate Cancer (NCI 03-C-0176A)
P.I.: Philip M. Arlen, M.D., LTIB, MOB; Protocol Chair: James L. Gulley, M.D., Ph.D., LTIB, MOB; Associate Investigator: William Dahut, M.D., MOB, NCI

A Phase II Study of Sequential Vaccinations with rFowlpox-PSA (L155) TRICOM (PROSTVAC-F/TRICOM) Alone or in Combination with rVaccinia-PSA (L155) TRICOM (PROSTVAC-V/TRICOM) and the Role of GM-CSF, in Patients with Prostate Cancer (NCI 03-C-0176B)
P.I.: Philip M. Arlen, M.D., LTIB, MOB; Protocol Chair: James L. Gulley, M.D., Ph.D., LTIB, MOB; Associate Investigator: William Dahut, M.D., MOB, NCI


Clinical Trials Group: J. Gulley, M.D., Ph.D., is P.I. or Protocol Chairman

IN PROGRESS:

Phase I Trial of a PSA-based Vaccine and an Anti-CTLA-4 Antibody in Patients with Metastatic Androgen Independent Prostate Cancer (NCI 05-C-0167)
P.I.: James L. Gulley, M.D., Ph.D., LTIB, MOB; Protocol Chair: Philip M. Arlen, M.D., LTIB, MOB; Associate Investigator: William Dahut, M.D., MOB, NCI

A Phase I Feasibility Study of an Intraprostatic PSA-based Vaccine in Prostate Cancer Patients with Local Failure Following Radiotherapy or Clinical Progression on Androgen Deprivation Therapy in the Absence of Local Definitive Therapy (NCI 05-C-0017)
P.I.: James L. Gulley, M.D., Ph.D., LTIB, MOB; Protocol Chair: Peter Pinto, M.D., Urologic Oncology Branch, NCI; Associate Investigator: Philip M. Arlen, M.D., LTIB, MOB

An Open Label Pilot Study to Evaluate the Safety and Tolerability of PANVACTM-V (vaccinia) and PANVACTM-F (fowlpox) in Combination with Sargramostim in Patients with Metastatic Carcinoma: Ovarian Cancer and Breast Cancer Specific (NCI 04-C-0246B)
P.I.: James L. Gulley, M.D., Ph.D., LTIB, MOB; Chair: Philip M. Arlen, M.D., LTIB, MOB

A Pilot Trial of a CEA-TRICOM-based Vaccine and Radiation to Liver Metastasis in Patients with CEA Positive Solid Tumors (NCI 04-C-0167)
P.I.: James L. Gulley, M.D., Ph.D., LTIB, MOB; Protocol Chair: Kevin Camphausen, M.D., Radiation Oncology Branch, NCI; Associate Investigator: Philip M. Arlen, M.D., LTIB, MOB

A Randomized Phase 2.5 Study of 153Sm-EDTMP (Quadramet) with or without a PSA TRICOM Vaccine in Patients with Androgen Insensitive Metastatic Prostate Cancer (NCI-07-C-0106)
P.I.: James L. Gulley, M.D., Ph.D., LTIB, MOB; Associate Investigators: Philip M. Arlen, M.D., LTIB, MOB, Jorge Carrasquillo, M.D., NIH Nuclear Medicine

IN REVIEW:

A Randomized, Placebo Controlled Phase II Trial of Limited Gonadotropin-Releasing Hormone Agonist Therapy with or without Vaccine (Onyvax) in Patients with D0 Prostate Cancer
P.I.: James L. Gulley, M.D., Ph.D., LTIB, MOB; Associate Investigators: Philip M. Arlen, M.D., LTIB, MOB, William Dahut, M.D., MOB, NCI

RECENTLY COMPLETED:

A Randomized Phase II Study of a PSA-based Vaccine in Patients with Localized Prostate Cancer Receiving Standard Radiotherapy (NCI 00-C-0154A)
P.I.: William Dahut, M.D., MOB, NCI; Author and Protocol Chairperson: James L. Gulley, M.D., Ph.D., LTIB, MOB (Gulley et al., Clin Ca Res, 2005); Associate Investigators: Philip M. Arlen, M.D., LTIB, MOB, C. Norman Coleman, M.D., Radiation Oncology Branch, NCI

A Randomized Phase II Study of a PSA-based Vaccine in Patients with Localized Prostate Cancer Receiving Standard Radiotherapy. Evaluation of Metronomic IL-2 (NCI 00-C-0154B)
P.I.: William Dahut, M.D., MOB, NCI; Author and Protocol Chairperson: James L. Gulley, M.D., Ph.D., LTIB, MOB; Associate Investigators: Philip M. Arlen, M.D., LTIB, MOB, C. Norman Coleman, M.D., Radiation Oncology Branch, NCI

An Open Label Pilot Study to Evaluate the Safety and Tolerability of PANVACTM-V (Vaccinia) and PANVACTM-F (Fowlpox) in Combination with Sargramostim in Patients with Metastatic Carcinoma (NCI 04-C-0246A)
P.I.: James L. Gulley, M.D., Ph.D., LTIB, MOB; Protocol Chair: Philip M. Arlen, M.D., LTIB, MOB
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MOB = Medical Oncology Branch



CLINICAL TRIALS CONTACT INFORMATION

For initial patient referrals, contact Mary Pazdur, N.P., the clinical trials liaison between patients and the physicians, at: Phone: 301-496-7870; Fax: 301-480-5094; E-mail: pazdurm@mail.nih.gov. For detailed information about these studies, including inclusion and exclusion factors, contact the principal investigator (see link on first page of Lab pages). For more information about the vaccines used in these trials, click on the links under Scientists and Clinicians on the first page of Lab pages.
For more information, go to the National Cancer Institute Clinical Trials Web site.


V. POSITION AVAILABLE

Senior Staff Scientist Position, Cellular/Molecular Immunology

The Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, is seeking a highly motivated Staff Scientist with expertise in cellular/molecular immunology to join the Laboratory's translational research program in cancer immunotherapy, with emphasis on the development of novel vaccines and vaccine strategies for the therapy of cancer. The applicant should have an interest in the study of immune cell/tumor cell interactions, mechanisms of immune cell activation, and strategies to enhance vaccine-mediated approaches for cancer therapy. The successful scientist will have the opportunity to supervise, with the Laboratory Chief, postdoctoral fellows and support staff, and will interact with other Laboratory scientists.

Minimum qualifications for this position include a Ph.D. and/or M.D. with at least 3 years of relevant experience in cellular/molecular immunology at the postdoctoral level, with sufficient publications to qualify for a Staff Scientist appointment. Salary is commensurate with experience and accomplishments, and a full civil service package of benefits (including retirement, health and life insurance, as well as thrift savings plan, etc.) is available. U.S. citizenship is not required.

Applicants should submit a CV, bibliography, and a brief statement of research interests, and arrange for three letters of recommendation to be sent to Ms. Robin Riley, Executive Secretary of Search Committee, LTIB, NIH, via e-mail at rr88f@nih.gov or post: Ms. Riley, 10 Center Drive, Room 8B09, NIH, Bethesda, MD 20892. Applications must be postmarked or received by email by July 30, 2008.
HHS/NIH/NCI are Equal Opportunity Employers


Please See "Links" for a List of Publications of the LTIB.

This page was last updated on 11/20/2008.