Amarillo, TX, United States
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Gupta P.,Texas Tech University Health Sciences Center | Wright S.E.,Texas Tech University Health Sciences Center | Wright S.E.,Harrington Cancer Center | Srivastava S.K.,Texas Tech University Health Sciences Center
OncoImmunology | Year: 2015

Breast tumors are heterogeneous with a complex etiology. The immune system plays a crucial role in the development of tumors and can facilitate tumor growth pleiotropically. Myeloid derived suppressor cells (MDSCs) generate reactive oxygen species (ROS) and cytokines to suppress T cells, dendritic cells and natural killer (NK) cells. Hence, the inhibition of MDSCs could be an important strategy for anticancer therapeutics. Phenethyl isothiocyanate (PEITC), a bioactive compound present in cruciferous vegetables, is known to have anticancer properties. However, the effects of PEITC administration on the immune system have not been previously reported. In the current study, we evaluated the effects of administering PEITC to immunocompromised NOD-SCID IL2Rγ-/-(SCID/NSG) host mice bearing MDA-MB-231 xenografts on MDSCs in the peripheral blood. Our results reveal that oral administration of 12 μmol PEITC attenuated tumor growth by 76%. This was marked tumor-inhibitory phenotype was associated with asignificant reduction in the levels of MDSCs bearing the surface markers CD33, CD34 and CD11b in PEITC treated mice, indicating that overall tumor growth suppression by PEITC correlates with inhibition of MDSCs. To the best of our knowledge, this is the first study showing effects of PEITC on MDSCs. © 2015 Taylor & Francis Group, LLC.


Wright S.E.,Amarillo Veterans Affairs Health Care System 111 | Wright S.E.,Womens Health and Research Institute | Wright S.E.,Texas Tech University Health Sciences Center | Wright S.E.,Harrington Cancer Center | And 13 more authors.
Journal of Immunotherapy | Year: 2012

The objective was to evaluate the toxicity and feasibility of intraperitoneal infusion of tumor-specific cytotoxic T lymphocytes (CTL) as therapy for recurrent ovarian cancer, and to determine if repetitive cycles of CTL generation and infusion measurably increases the host's ovarian cancer immune response. In this study, 7 subjects with recurrent ovarian cancer confined to the peritoneal cavity underwent up to 4 cycles, each cycle beginning with a leukapheresis for collection of precursor lymphocytes, which were stimulated in vitro with mucin 1, a tumor-specific antigen found commonly in ovarian cancer cells. The resulting new CTL for each cycle were reintroduced into the host by intraperitoneal infusion. Immunologic parameters (killer cells, cytokine production, memory T lymphocytes, and natural killer cells) were studied. Toxicity, CA-125, and survival data were also evaluated. The tumor marker CA-125 was nonstatistically significantly reduced after the first month of immunotherapy. However, after that it rose. Killer cells, cytokine production, and memory T lymphocytes increased after the first cycle of stimulation, but plateaued or reduced thereafter. The percent of natural killer cells inversely correlated with other immune parameters. Median survival was 11.5 months. One subject is free of disease since December, 2000. Multiple cycles, beyond 1 cycle, of T-cell stimulation followed by adoptive T-cell infusion, may not enhance the in vivo immune response. Copyright © 2012 by Lippincott Williams & Wilkins.


Ballard K.S.,East Carolina University | Tedjarati S.S.,Texas Tech University Health Sciences Center | Robinson W.R.,Texas Tech University Health Sciences Center | Robinson W.R.,Harrington Cancer Center | And 2 more authors.
International Journal of Gynecological Cancer | Year: 2010

The aim of this retrospective study was to evaluate differences in treatment of embryonal rhabdomyosarcoma (RMS) of the uterus in 2 premenopausal women. We discuss adjuvant chemotherapy and use of ChemoFx Assay (Precision Therapeutics, Pittsburgh, PA) to guide choice of active chemotherapeutic agents. Two premenopausal patients were identified with a pathologic diagnosis of embryonal RMS of the uterus. Both met inclusion criteria for the study. A 21-year-old woman underwent a staging abdominal hysterectomy for a variant of embryonal RMS. Vincristine, actinomycin D, and cyclophosphamide were given adjunctively for a complete response. A 20-year-old woman underwent a diagnostic dilation and curettage revealing embryonal RMS. Initial treatment included an abdominal hysterectomy and nodal sampling. Presentation to a subsequent gynecologic oncologist 7 months later revealed recurrence. Carboplatin, doxorubicin, and paclitaxel provided a partial response. After a second surgical resection, ChemoFx Assay identified ifosfamide and mitomycin C as active agents and resulted in a complete response. Recommended treatment includes surgery and chemotherapy with possible radiation therapy if deemed necessary. The benefit of adding neoadjuvant or adjuvant chemotherapy and radiation therapy allows for a conservative surgical approach and improved survival. Choosing active chemotherapy agents can be aided by ChemoFx Assay. The chemotherapy most commonly used for treatment of embryonal RMS is a combination of vincristine, actinomycin D, and cyclophosphamide.


Wright S.E.,Womens Health Research Institute | Wright S.E.,Harrington Cancer Center | Rewers-Felkins K.A.,Womens Health Research Institute | Quinlin I.,Womens Health Research Institute | And 5 more authors.
Oncology Letters | Year: 2014

The aim of the present study was to determine whether the combination of two modalities of immunotherapy, targeting two different tumor antigens, may be feasible and non-toxic, yet enhance the killing of a human breast cancer cell line. The first modality was tumor growth factor α-Pseudomonas exotoxin 38 (TGFα-PE38), which specifically targets and kills tumor cells that express the epidermal growth factor receptor. The second modality was mucin-1 (MUC1)-specific cytotoxic T lymphocytes (CTLs), generated by MUC1 stimulation of peripheral blood mononuclear cells, to target the human breast cancer cell line, MCF7. TGFα-PE38 exhibited specific lysis of the MCF7 cells in a concentration-and time-dependent manner. TGFα-PE38 did not kill the normal hematopoietic stem cells or CTLs. Furthermore, TGFα-PE38 was not inhibitory for the growth or differentiation of the normal human hematopoietic stem cells into erythroid and myeloid colonies. In addition, TGFα-PE38 did not inhibit the killing function of CTLs, either when preincubated or co-incubated with CTLs. Finally, therapeutic enhancement was observed, in that TGFα-PE38 and CTLs were additive in the specific lysis of the MCF7 cells. These two modalities of immunotherapy may be beneficial for humans with breast cancer with or without other therapies, including autologous hematopoietic stem cell transplantation, specifically for purging cancer cells from hematopoietic stem cells prior to transplantation.


Wright S.E.,Womens Health Research Institute | Wright S.E.,Texas Tech University Health Sciences Center | Wright S.E.,Harrington Cancer Center | Rewers-Felkins K.A.,Womens Health Research Institute | And 3 more authors.
Oncology Letters | Year: 2016

Cytotoxic T-lymphocyte activation and extension of the cell life span is necessary in order to enable immunotherapy to perform effectively against cancer. In the present study, mucin 1 (MUC1)-stimulated human mononuclear cells (M1SHMCs) were costimulated with bead-attached monoclonal antibodies specific for cluster of differentiation (CD)3 and CD28 receptors. The study was undertaken to determine whether costimulation was capable of enhancing the killing of cancer cells in vitro and of protecting non-obese diabetic severe combined immunodeficient mice from tumor development. Lysis of MCF-7 tumor cells by M1SHMCs was reduced following costimulation with anti-CD3 and anti-CD28. Furthermore, costimulation with anti-CD3 and anti-CD28 eliminated the protective effects of M1SHMCs on MCF-7 breast cancer cell growth in the non-obese diabetic severe combined immunodeficient mice. The present study suggested that costimulation with anti-CD3 and anti-CD28 is not advisable following antigen activation of lymphocytes under the conditions used here. Using a lower anti-CD3/CD28 bead to T-cell ratio may prevent immune suppression, however, further studies are required to support this hypothesis. © Spandidos Publications 2015. All rights reserved.


PubMed | Harrington Cancer Center, Texas Tech University Health Sciences Center and U.S. National Institutes of Health
Type: Journal Article | Journal: Oncology letters | Year: 2014

The aim of the present study was to determine whether the combination of two modalities of immunotherapy, targeting two different tumor antigens, may be feasible and non-toxic, yet enhance the killing of a human breast cancer cell line. The first modality was tumor growth factor -


Wright S.E.,Amarillo Veterans Affairs Health Care System | Wright S.E.,Texas Tech University Health Sciences Center | Wright S.E.,Harrington Cancer Center
Expert Opinion on Biological Therapy | Year: 2012

Introduction: Immunotherapy of breast cancer has been shown to prevent recurrence, improve survival and eliminate breast cancer in humans. Areas covered: The reason for this review is to present the current information and the prospects for the future of immunotherapy of breast cancer in humans to include tumor antigens for vaccines and targets for monoclonal antibodies and adoptive T-cell therapy, and immune modulatory agents, such as adjuvants to stimulate the immune response and inhibitors of checkpoint blockade to prevent downmodulation of activated lymphocytes, to enhance these modalities. The research discussed and the literature search undertaken is of the clinical immunotherapy of breast cancer in humans, from 2000 to September, 2011. Expert opinion: The key message of the paper is that one reason for the failure of the immune system to control macroscopic disease is that the immune escape mechanisms involving both tumor and the tumor stroma prevent the immune system from destroying the tumor. Changing the tumor microenvironment is necessary to eliminate macroscopic tumors. Prospects for improvement are proposals for combining current modalities of therapy with type 1 cellular immunity-inducing agents, all targeting multiple tumor antigens and in the context of minimal disease. © 2012 Informa UK, Ltd.


Dobrzanski M.J.,Texas Tech University | Dobrzanski M.J.,Bristol Hospital Cancer Care Center | Rewers-Felkins K.A.,Texas Tech University | Samad K.A.,Texas Tech University | And 8 more authors.
Cancer Immunology, Immunotherapy | Year: 2012

Adoptive T cell therapy for cancer patients optimally requires participation of CD4 T cells. In this phase I/II study, we assessed the therapeutic effects of adoptively transferred IL-10- and IFN-γ-producing CD4 effector cells in patients with recurrent ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4 effector cell generation, we show that three monthly treatment cycles of autologous T cell restimulation and local intraperitoneal re-infusion-modulated T cell-mediated immune responses that were associated with enhanced patient survival. One patient remains disease-free, another patient experienced prolonged survival for nearly 16 months with recurrent disease, and two patients expired within 3-5 months following final infusion. Prolonged survivors showed elevated levels of systemic CD3 +CD4 +CD25 + and CD3 +CD4 +CD25 - T cells when compared to that of pre-treatment levels and similarly treated short-term survivors. Such cell populations among these patients contained variable levels of "Inducible" Tr1 (CD4 +CD25 -FoxP3 -IL-10 +) and "Natural" (CD4 +CD25 +CD45RO +FoxP3 +) TReg cell numbers and ratios that were associated with prolonged and/or disease-free survival. Moreover, peptide-restimulated T cells from these patients showed an elevation in both IFN-γ production, memory cell phenotype, and select TNF family ligands associated with enhanced T cell survival and apoptosis-inducing activities. This suggests that intraperitoneally administered Th1-like cells, producing elevated levels of IL-10, may require and/or induce differential levels of distinct systemic TReg subpopulations that influence, in part, long-term tumor immunity and enhanced memory/effector CD4-mediated therapeutic potentials. Furthermore, treatment efficacy and enhanced memory cell phenotype did not appear to be dependent on TReg cell numbers but upon ratios of "Inducible" and "Natural" TReg subpopulations. © 2011 Springer-Verlag.


Wright S.E.,Texas Tech University Health Sciences Center | Wright S.E.,Harrington Cancer Center | Rewers-Felkins K.A.,Texas Tech University Health Sciences Center | Chowdhury N.I.,Texas Tech University Health Sciences Center | And 2 more authors.
Oncology Letters | Year: 2012

CpG-ODNs activate various immune cell subsets and induce the production of numerous cytokines. To determine whether a CpG-ODN-activated innate immune system, without the adaptive immune system, was capable of protecting against cancer cell growth, NOD/SCID mice, which do not have T or B cell function but have a functional innate immune system, were used as a model system. NOD/SCID mice were injected subcutaneously with human prostate cancer cells followed by subcutaneous injection of incremental doses of CpG-ODNs. CpG-ODNs displayed a dose-related antitumoral effect leading to the prevention of tumor growth. These results indicate that ODNs are capable of activating the innate immune system and destroying human cancer cells in the absence of the adaptive immune system.


Wang Z.,Texas Tech University Health Sciences Center | Wang Z.,West Texas A&M University | Hall M.D.,Texas Tech University Health Sciences Center | Hall M.D.,West Texas A&M University | And 7 more authors.
OncoImmunology | Year: 2013

Dendritic cells (DCs) are among the most potent antigen-presenting cells (APCs), stimulating peripheral blood mononuclear cells (PBMCs) to generate antigen-specific cytotoxic T lymphocytes (CTLs). The objectives of this study were to determine if interleukin (IL)-4 is beneficial or detrimental for the generation of human DCs in vitro and to understand whether DCs generated in vitro in the presence or absence of IL-4 stimulate the killing of adenocarcinoma cells by CTLs in vivo. Mucin 1 (MUC1), a glycoprotein found on the surface of adenocarcinoma cells was used to load DCs. MUC1-loaded DCs generated in the absence of IL-4 were superior to their counterparts produced with IL-4 in stimulating PBMCs to kill human breast cancer MCF-7 cells in vitro. A corollary in vivo protection experiment was performed by injecting immunodeficient NOD-SC ID mice with MCF-7 cells s.c. and MUC1-loaded CTLs, PBMCs, or DCs generated in the absence of IL-4, i.p. Mice that received CTLs and MUC1-loaded DCs on days 0, 2, 4, 9, 14 and 19 were completely protected against the development of MCF-7-derived tumors, while other schedules conferred lower protection. Therefore, tumor antigen-loaded DCs enhance the efficacy of adoptive CTL transfer, and should thus be considered for combinatorial immunotherapeutic regimens. © 2013 Landes Bioscience.

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