Journal Articles

Conventional therapies

Immunological effects of conventional cancer therapies such as chemotherapy, radiotherapy or targeted therapy

p53-reactive T cells are associated with clinical benefit in patients with platinum-resistant epithelial ovarian cancer after treatment with a p53 vaccine and gemcitabine chemotherapy

More

PURPOSE: To conduct a Phase I trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer. EXPERIMENTAL DESIGN: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses. RESULTS: 11 patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome and immunological response. TOXICITY: There were no DLTs but 3/11 patients came off study early due to gemcitabine-attributed adverse events (AEs). Minimal AEs were attributed to p53MVA vaccination. Immunological and Clinical Response: Enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T cell compartments in 5/11 and 6/11 patients respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity post therapy. Tumor shrinkage or disease stabilization occurred in 4 patients. CONCLUSIONS: p53MVA was well tolerated, but gemcitabine without steroid pre-treatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+T cell responses post therapy correlated with longer PFS. Therefore, if responses to p53MVA could be enhanced with alternative agents, superior clinical responses may be achievable.

Author Info: (1) Experimental Therapeutics, City of Hope. (2) Department of Information Sciences, City of Hope. (3) Information Sciences, City of Hope National Medical Center. (4) Department

Author Info: (1) Experimental Therapeutics, City of Hope. (2) Department of Information Sciences, City of Hope. (3) Information Sciences, City of Hope National Medical Center. (4) Department of Medical Oncology and Therapeutics Research, City Of Hope National Medical Center. (5) Hematology/Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center. (6) Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope. (7) Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope. (8) Ps Medical Oncology, City of Hope. (9) Department of Medical Oncology and Therapeutics Research, City Of Hope National Medical Center. (10) Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center. (11) Clinical Trials Office, City of Hope National Medical Center. (12) Clinical Trials Office, City Of Hope National Medical Center. (13) Antatomy Pathology, City of Hope National Medical Center. (14) General & Oncologic Surgery, City of Hope National Medical Center. (15) Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope ddiamond@coh.org. (16) Medical Oncology and Therapeutic Research, City of Hope.

Less

A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors

More

The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-gamma-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.

Author Info: (1) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (2) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (3) ARO

Author Info: (1) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (2) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (3) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (4) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (5) Department of Anatomic Pathology, Pathological Sciences, Kyushu University, Fukuoka, Japan. (6) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (7) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (8) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (9) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (10) Research Institute of Diseases of Chest, Kyushu University, Fukuoka, Japan. (11) Department of Anatomic Pathology, Pathological Sciences, Kyushu University, Fukuoka, Japan. (12) Human genome center, Institute of medical science, University of Tokyo, Tokyo, Japan. (13) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. Project Division of ALA Advanced Medical Research, Advanced Medical Science of Internal Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Less

Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer

More

Successful development of immunotherapeutic strategies for hepatocellular cancer (HCC) has been impeded by limited understanding of tumor-induced profound tolerance and lack of a clinically faithful HCC model. Recently, we developed a novel model that recapitulates typical features of human HCC. Using this clinically relevant model, we demonstrate that tumor growth impairs host immunity and causes a profound exhaustion of tumor antigen-specific (TAS) CD8(+) T cells. Increase in frequency and suppressive function of regulatory T cells (Tregs) is critically involved in this tumor-induced immune dysfunction. We further demonstrate that sunitinib suppresses Tregs and prevents tumor-induced immune tolerance, allowing TAS immunization to activate endogenous CD8(+) T cells. As a result, this combinational strategy delays tumor growth. Importantly, the additional integration of exogenous naive TAS CD8(+) T cells by adoptive cell transfer (ACT) leads to the elimination of the established tumors without recurrence and promotes long-term survival of the treated mice. Mechanistically, sunitinib treatment primes the antitumor immune response by significantly decreasing Treg frequency, reducing TGF-beta and IL-10 production by Tregs, and also protecting TAS CD8(+) T cells from tumor-induced deletion in the setting of HCC. Taken together, sunitinib quantitatively and qualitatively modifies Tregs to overcome tumor-induced immune deficiency, suggesting the potential of sunitinib as a therapeutic immune activator for HCC control.

Author Info: (1) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. (2) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Department of Microbiology and Immunology

Author Info: (1) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. (2) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Department of Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO, USA. (3) Department of Surgery, University of Chicago, IL, USA. (4) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (5) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (6) Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (7) Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA. (8) Department of Surgery, Medical University of South Carolina, Charleston, SC, USA; Department of Medicine, Medical University of South Carolina, Charleston, SC, USA. (9) Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, USA. (10) Department of Surgery, University of Missouri-Columbia, Columbia, MO, USA. Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, USA.

Less

Immunotherapy for glioblastoma: on the sidelines or in the game

More

The successful eradication of multiple tumor types, often in a durable manner, has recently validated the bona fide potential of an effectively mobilized immune response as a cancer therapy. Critical questions at present, therefore, include deciphering why some patients respond while others do not, as well as why certain cancers respond while others like glioblastoma do not. Glioblastoma remains a major unmet need in medical oncology and is considered incurable with less than 10% of patients surviving five years from diagnosis. Hallmark phenotypic features of glioblastoma including aberrantly activated cell proliferation, survival, invasion, angiogenesis, and treatment resistance are linked with multiple adaptive and supportive mechanisms culminating in formidable heterogeneity across and within individual tumors. Similarly, the complex adaptive abilities of glioblastoma tumors to abrogate anti-tumor immune responses are multifaceted yet integrated. Not unexpectedly, results of recent advanced clinical trials with single-agent immunotherapeutics for glioblastoma have been negative although some early stage studies and anecdotal cases have generated encouraging results. The application of immunotherapies for glioblastoma currently finds itself therefore at a pivotal crossroads. Critical to mapping a path forward will be the systematic characterization of the immunobiology of glioblastoma tumors utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector immune cells into the glioblastoma microenvironment as well as overcoming immunosuppressive myeloid cells, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of dexamethasone, will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma.

Author Info: (1) Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215

Author Info: (1) Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. (3) Department of Neurosurgery, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA.

Less

Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers

More

Over the past few years, multiple immune checkpoint blockers (ICBs) have achieved unprecedented clinical success and have been approved by regulatory agencies for the treatment of an increasing number of malignancies. However, only a limited fraction of patients responds to ICBs employed as a standalone intervention, calling for the development of combinatorial regimens. Radiation therapy (RT) stands out as a very promising candidate for this purpose. Indeed, RT mediates antineoplastic effects not only by cytotoxic and cytostatic mechanisms, but also by modulating immunological functions, both locally (within the irradiated field) and systemically. As combinatorial regimens involving RT and ICBs are being developed and clinically tested at an accelerating pace, it is paramount to identify biomarkers that reliably predict the likelihood of individual patients to respond. Here, we discuss emerging biomarkers that may potentially predict the response of cancer patients to RT plus ICBs.

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. (2) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY

Author Info: (1) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. (2) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. (3) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA. (4) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA. (5) Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address: szd3005@med.cornell.edu.

Less

A pilot study of an autologous tumor-derived autophagosome vaccine with docetaxel in patients with stage IV non-small cell lung cancer

More

BACKGROUND: Tumor-derived autophagosome vaccines (DRibbles) have the potential to broaden immune response to poorly immunogenic tumors. METHODS: Autologous vaccine generated from tumor cells harvested from pleural effusions was administered to patients with advanced NSCLC with the objectives of assessing safety and immune response. Four patients were vaccinated and evaluable for immune response; each received two to four doses of vaccine. Study therapy included two cycles of docetaxel 75 mg/m(2) on days 1 and 29 to treat the tumor, release hidden antigens and produce lymphopenia. DRibbles were to be administered intradermally on days 14, 43, 57, 71, and 85, together with GM-CSF (50 mug/d x 6d, administered via SQ mini pump). Peripheral blood was tested for immune parameters at baseline and at each vaccination. RESULTS: Three of four patients had tumor cells available for testing. Autologous tumor-specific immune response was seen in two of the three, manifested by IL-5 (1 patient after 3 doses), and IFN-gamma, TNF-alpha, IL-5, IL-10 (after 4 doses in one patient). All 4 patients had evidence of specific antibody responses against potential tumor antigens. All patients came off study after 4 or fewer vaccine treatments due to progression of disease. No significant immune toxicities were seen during the course of the study. CONCLUSIONS: DRibble vaccine given with GM-CSF appeared safe and capable of inducing an immune response against tumor cells in this small, pilot study. There was no evidence of efficacy in this small poor-prognosis patient population, with treatment not feasible. Trial registration NCT00850785, initial registration date February 23,

Author Info: (1) Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. Rachel.sanborn@providence.org. Earle A. Chiles Research Institute

Author Info: (1) Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. Rachel.sanborn@providence.org. Earle A. Chiles Research Institute, N.E. Glisan Street, 2N35, Portland, OR, 97213, USA. Rachel.sanborn@providence.org. (2) Mayo Clinic Arizona, Phoenix, AZ, USA. (3) UbiVac, Portland, OR, USA. Present address: Nektar Therapeutics, San Francisco, USA. (4) Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. (5) Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. (6) Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. (7) UbiVac, Portland, OR, USA. (8) Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. (9) Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. (10) Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. (11) Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. Present address: Department of General, Visceral and Transplantation Surgery, University of Munich, Campus Grosshadern, Munich, Germany. (12) Immunological Monitoring Laboratory, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. (13) UbiVac, Portland, OR, USA. Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. (14) Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. (15) UbiVac, Portland, OR, USA. Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. Department of Molecular Microbiology and Immunology; and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.

Less

Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies

More

The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)-based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.

Author Info: (1) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. Electronic address: ishiih@yamanashi.ac.jp. (2) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi

Author Info: (1) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. Electronic address: ishiih@yamanashi.ac.jp. (2) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi; Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine. (3) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (4) Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine. (5) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (6) Division of Transfusion Medicine and Cell Therapy, University of Yamanashi Hospital. (7) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (8) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. (9) Department of Otolaryngology, Head and Neck Surgery, University of Yamanashi. Electronic address: mkeisuke@yamanashi.ac.jp.

Less

The Effect of Topoisomerase I Inhibitors on the Efficacy of T-Cell-Based Cancer Immunotherapy

More

Background: Immunotherapy has increasingly become a staple in cancer treatment. However, substantial limitations in the durability of response highlight the need for more rational therapeutic combinations. The aim of this study is to investigate how to make tumor cells more sensitive to T-cell-based cancer immunotherapy. Methods: Two pairs of melanoma patient-derived tumor cell lines and their autologous tumor-infiltrating lymphocytes were utilized in a high-throughput screen of 850 compounds to identify bioactive agents that could be used in combinatorial strategies to improve T-cell-mediated killing of tumor cells. RNAi, overexpression, and gene expression analyses were utilized to identify the mechanism underlying the effect of Topoisomerase I (Top1) inhibitors on T-cell-mediated killing. Using a syngeneic mouse model (n = 5 per group), the antitumor efficacy of the combination of a clinically relevant Top1 inhibitor, liposomal irinotecan (MM-398), with immune checkpoint inhibitors was also assessed. All statistical tests were two-sided. Results: We found that Top1 inhibitors increased the sensitivity of patient-derived melanoma cell lines (n = 7) to T-cell-mediated cytotoxicity (P < .001, Dunnett's test). This enhancement is mediated by TP53INP1, whose overexpression increased the susceptibility of melanoma cell lines to T-cell cytotoxicity (2549 cell line: P = .009, unpaired t test), whereas its knockdown impeded T-cell killing of Top1 inhibitor-treated melanoma cells (2549 cell line: P < .001, unpaired t test). In vivo, greater tumor control was achieved with MM-398 in combination with alpha-PD-L1 or alpha-PD1 (P < .001, Tukey's test). Prolonged survival was also observed in tumor-bearing mice treated with MM-398 in combination with alpha-PD-L1 (P = .002, log-rank test) or alpha-PD1 (P = .008, log-rank test). Conclusions: We demonstrated that Top1 inhibitors can improve the antitumor efficacy of cancer immunotherapy, thus providing the basis for developing novel strategies using Top1 inhibitors to augment the efficacy of immunotherapy.

Author Info: (1) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (2) Department of Melanoma Medical Oncology, The University of

Author Info: (1) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (2) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (3) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (4) Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX. (5) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (6) Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (7) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (8) Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX. (9) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (10) Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. (11) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (12) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (13) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (14) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (15) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (16) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (17) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (18) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (19) Department of Cancer Imaging Systems, The University of Texas MD Anderson Cancer Center, Houston, TX. (20) Department of Cancer Imaging Systems, The University of Texas MD Anderson Cancer Center, Houston, TX. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (22) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (23) Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX. (24) Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. Center for RNA Interference and Non-coding RNA,The University of Texas MD Anderson Cancer Center, Houston, TX. (25) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX. (26) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. (27) Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX). (28) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Less

Cross Talk between Radiation and Immunotherapy: The Twain Shall Meet

More

There has been increased interest in the immune stimulatory properties of ionizing radiation based on several preclinical models and recently completed clinical studies performed in combination with checkpoint inhibitors. This is a paradigm shift in that it considers the role of radiation beyond its direct cytotoxic effects, however, the factors that promote or limit radiation-induced immunogenicity are still unclear. Here we review the role of radiation in modulating the various aspects of the tumor immune microenvironment and discuss in particular the direct effects of radiation on the DNA damage response and its immediate consequences to neighboring cells. The latter "danger response" in particular can enhance recruitment of dendritic and macrophage cells to the tumor microenvironment, which in turn can activate or diminish subsequent T-cell priming. Identification of the critical factors that modulate the interaction between radiation-induced cell damage and the immune system will allow for rational combinational therapy design and the development of biomarkers that predict effective immune responses.

Author Info: (1) a Department of Hematology, Houston Methodist Cancer Center and. (2) b Department of Radiation Oncology, The Houston Methodist Research Institute, Weil Cornell Medical College

Author Info: (1) a Department of Hematology, Houston Methodist Cancer Center and. (2) b Department of Radiation Oncology, The Houston Methodist Research Institute, Weil Cornell Medical College, Houston Texas 77030 . (3) b Department of Radiation Oncology, The Houston Methodist Research Institute, Weil Cornell Medical College, Houston Texas 77030 .

Less

Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms

More

Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors (PNET) that developed spontaneously and progress as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI). These effects were not mimicked by selective inhibition of VEGFR-2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells (Tregs) and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by co-administration of sunitinib.

Author Info: (1) Anatomy, UCSF. (2) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (3) Comprehensive Cancer Center and Dept of Anatomy, Univ

Author Info: (1) Anatomy, UCSF. (2) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (3) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (4) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (5) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (6) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (7) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (8) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (9) Ottawa Health Research Institute, Centre for Cancer Therapeutics. (10) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco. (11) Cancer Therapeutics, Ottawa Hospital Research Institute. (12) CEO, 4D Molecular Therapeutics. (13) Cancer Therapeutics, Ottawa Hospital Research Institute. (14) Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute. (15) Biotherapeutics, SillaJen. (16) Comprehensive Cancer Center and Dept of Anatomy, Univ of California, San Francisco donald.mcdonald@ucsf.edu.

Less