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Lana E Kandalaft,
Daniel J Powell Jr,
Cheryl L Chiang,
Janos Tanyi,
Sarah Kim,
Marnix Bosch,
Kathy Montone,
Rosemarie Mick,
Bruce L Levine,
Drew A Torigian,
Carl H June,
George Coukos
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ABSTRACT: Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 109 autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8+ lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes.
Oncoimmunology. 01/2013; 2(1):e22664.
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ABSTRACT: PURPOSE: In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. RATIONALE: Genetically reprogrammed, patient-derived chimeric antigen receptor (CAR)-T lymphocytes with the ability to recognize predefined surface antigens with high specificity in a non-MHC restricted manner have shown increasing anti-tumor efficacy in preclinical and clinical studies. Folate receptor-α (FRα) is an ovarian cancer-specific tumor target; however, it is expressed at low levels in certain organs with risk for toxicity. DESIGN: Here we propose a phase I study testing the feasibility, safety and preliminary activity of FRα-redirected CAR-T cells bearing the CD137 (4-1BB) costimulatory domain, administered after lymphodepletion for the treatment of recurrent ovarian cancer. A novel trial design is proposed that maximizes safety features. INNOVATION: This design involves an initial accelerated dose escalation phase of FR-α CAR-T cells followed by a standard 3 + 3 escalation phase. A split-dose approach is proposed to mitigate acute adverse events. Furthermore, infusion of bulk untransduced autologous peripheral blood lymphocytes (PBL) is proposed two days after CAR-T cell infusion at the lower dose levels of CAR-T cells, to suppress excessive expansion of CAR-T cells in vivo and mitigate toxicity.
Journal of Translational Medicine 08/2012; 10:157. · 3.41 Impact Factor
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ABSTRACT: Led by key opinion leaders in the field, the Cancer Immunotherapy Consortium of the Cancer Research Institute 2012 Scientific Colloquium included 179 participants who exchanged cutting-edge information on basic, clinical and translational cancer immunology and immunotherapy. The meeting revealed how rapidly this field is advancing. The keynote talk was given by Wolf H Fridman and it described the microenvironment of primary and metastatic human tumors. Participants interacted through oral presentations and panel discussions on topics that included host reactions in tumors, advances in imaging, monitoring therapeutic immune modulation, the benefit and risk of immunotherapy, and immune monitoring activities. In summary, the annual meeting gathered clinicians and scientists from academia, industry and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy.
Immunotherapy 08/2012; 4(8):761-72. · 1.85 Impact Factor
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ABSTRACT: In the past few years, cancer immunotherapies have produced promising results. Although traditionally considered unresponsive
to immune therapy, increasing evidence indicates that ovarian cancers are, in fact, immunogenic tumors. This evidence comes
from diverse epidemiologic and clinical data comprising evidence of spontaneous antitumor immune response and its association
with longer survival in a proportion of ovarian cancer patients; evidence of tumor immune evasion mechanisms and their association
with short survival in some ovarian cancer patients; and finally pilot data supporting the efficacy of immune therapy. Below
we will discuss lessons learned on the biology underlying ovarian cancer immune rejection or tolerance and we will discuss
its association with clinical outcome. We will discuss the role of angiogenesis and the tumor endothelium on regulation of
the antitumor immune response with a special emphasis on the role of vascular endothelial growth factor (VEGF) in the suppression
of immunological processes, which control tumor progression and its unique crosstalk with endothelin systems, and how their
interactions may shape the antitumor immune response. In addition, we will discuss mechanisms of tumor tolerance through the
suppression or exhaustion of effector cells and how these could be countered in the clinic. We believe that understanding
these pathways in the tumor microenvironment will lead to novel strategies for enhancing ovarian cancer immunotherapy.
KeywordsOvarian cancer–Tumor immunoserveillance
Cancer and metastasis reviews 04/2012; 30(1):141-151. · 10.57 Impact Factor
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ABSTRACT: Dendritic cells (DCs) are the most potent antigen-presenting cell population for activating tumor-specific T cells. Due to the wide range of methods for generating DCs, there is no common protocol or defined set of criteria to validate the immunogenicity and function of DC vaccines.
Monocyte-derived DCs were generated during 4 days of culture with recombinant granulocyte-macrophage colony stimulating factor and interleukin-4, and pulsed with tumor lysate produced by hypochlorous acid oxidation of tumor cells. Different culture parameters for clinical-scale DC preparation were investigated, including: 1) culture media; 2) culture surface; 3) duration of activating DCs with lipopolysaccharide (LPS) and interferon (IFN)-gamma; 4) method of DC harvest; and 5) cryomedia and final DC product formulation.
DCs cultured in CellGenix DC media containing 2% human AB serum expressed higher levels of maturation markers following lysate-loading and maturation compared to culturing with serum-free CellGenix DC media or AIM-V media, or 2% AB serum supplemented AIM-V media. Nunclon™Δ surface, but not Corning(®) tissue-culture treated surface and Corning(®) ultra-low attachment surface, were suitable for generating an optimal DC phenotype. Recombinant trypsin resulted in reduced major histocompatibility complex (MHC) Class I and II expression on mature lysate-loaded DCs, however presentation of MHC Class I peptides by DCs was not impaired and cell viability was higher compared to cell scraping. Preservation of DCs with an infusible cryomedia containing Plasma-Lyte A, dextrose, sodium chloride injection, human serum albumin, and DMSO yielded higher cell viability compared to using human AB serum containing 10% DMSO. Finally, activating DCs for 16 hours with LPS and IFN-γ stimulated robust mixed leukocyte reactions (MLRs), and high IL-12p70 production in vitro that continued for 24 hours after the cryopreserved DCs were thawed and replated in fresh media.
This study examined criteria including DC phenotype, viability, IL-12p70 production and the ability to stimulate MLR as metrics of whole oxidized tumor lysate-pulsed DC immunogenicity and functionality. Development and optimization of this unique method is now being tested in a clinical trial of autologous oxidized tumor lysate-pulsed DC in clinical-scale in recurrent ovarian, primary peritoneal or fallopian tube cancer (NCT01132014).
Journal of Translational Medicine 11/2011; 9:198. · 3.41 Impact Factor
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ABSTRACT: ABSTRACT: Cell and gene therapy clinical trials have been conducted for various indications such as cancer, cardiovascular diseases and autoimmune disorders for more than 20 years.
Journal of Translational Medicine 07/2011; 9(1):116. · 3.41 Impact Factor
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ABSTRACT: In the past few years, cancer immunotherapies have produced promising results. Although traditionally considered unresponsive to immune therapy, increasing evidence indicates that ovarian cancers are, in fact, immunogenic tumors. This evidence comes from diverse epidemiologic and clinical data comprising evidence of spontaneous antitumor immune response and its association with longer survival in a proportion of ovarian cancer patients; evidence of tumor immune evasion mechanisms and their association with short survival in some ovarian cancer patients; and finally pilot data supporting the efficacy of immune therapy. Below we will discuss lessons learned on the biology underlying ovarian cancer immune rejection or tolerance and we will discuss its association with clinical outcome. We will discuss the role of angiogenesis and the tumor endothelium on regulation of the antitumor immune response with a special emphasis on the role of vascular endothelial growth factor (VEGF) in the suppression of immunological processes, which control tumor progression and its unique crosstalk with endothelin systems, and how their interactions may shape the antitumor immune response. In addition, we will discuss mechanisms of tumor tolerance through the suppression or exhaustion of effector cells and how these could be countered in the clinic. We believe that understanding these pathways in the tumor microenvironment will lead to novel strategies for enhancing ovarian cancer immunotherapy.
CANCER AND METASTASIS REVIEW 02/2011; 30(1):141-51. · 9.35 Impact Factor
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ABSTRACT: Cancer immunotherapies have yielded promising results in recent years, but new approaches must be utilized if more patients are to experience the benefits of these therapies. Angiogenesis and the tumor endothelium confer unique immune privilege to a growing tumor, with significant effects on diverse immunological processes such as hematopoietic cell maturation, antigen presentation, effector T cell differentiation, cytokine production, adhesion, and T cell homing and extravasation. Here, we review the role of angiogenesis and the tumor endothelium on regulation of the antitumor immune response. We place particular emphasis on the role of vascular endothelial growth factor (VEGF) in the suppression of numerous immunological processes that control tumor progression. Further, we describe the unique crosstalk between the VEGF and endothelin systems, and how their interactions may shape the antitumor immune response. These insights establish new targets for combinatorial approaches to modify existing cancer immunotherapies.
Current topics in microbiology and immunology 01/2011; 344:129-48. · 4.93 Impact Factor
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ABSTRACT: "Day-7" myeloid DCs are commonly used in the clinic. However, there is a strong need to develop DCs faster that have the same potent immunostimulatory capacity as "Day-7" myeloid DCs and at the same time minimizing time, labor and cost of DC preparations. Although "2 days" DCs can elicit peptide-specific responses, they have not been demonstrated to engulf, process and present complex whole tumor lysates, which could be more convenient and personalized source of tumor antigens than defined peptides. In this preclinical study, we evaluated the T-cell stimulatory capacity of Day-2, Day-4, and Day-7 cultured monocyte-derived DCs loaded with SKOV3 cell whole lysate prepared by freeze-thaw or by UVB-irradiation followed by freeze-thaw, and matured with lipopolysaccharide (LPS) and interferon (IFN)-gamma. DCs were evaluated for antigen uptake, and following maturation with LPS and IFN-gamma, DCs were assessed for expression of CD80, CD40, CD86, ICAM-1 and CCR7, production of IL-12p70 and IP-10, and induction of tumor-specific T-cell responses. Day-4 and Day-7 DCs exhibited similar phagocytic abilities, which were superior to Day-2 DCs. Mature Day-7 DCs expressed the highest CD40 and ICAM-1, but mature Day-4 DCs produced the most IL-12p70 and IP-10. Importantly, Day-4 and Day-7 DCs derived from ovarian cancer patients stimulated equally strongly tumor-specific T-cell responses. This is the first study demonstrating the highly immunogenic and strong T-cell stimulatory properties of Day-4 myeloid DCs, and provided important preclinical data for rapid development of potent whole tumor lysate-loaded DC vaccines that are applicable to many tumor types.
PLoS ONE 01/2011; 6(12):e28732. · 4.09 Impact Factor
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ABSTRACT: Epithelial ovarian carcinoma (EOC) is the fourth most common cancer in women, and the most lethal gynecologic malignancy in
the United States, accounting for approximately 22,000 new cases and 15,000 deaths per year. Due to incremental improvements
in surgery and chemotherapy, the 5-year survival rate has increased from 37% in the 1970s to 45% in the 1990s (Bukowski et
al. 2007). Based on large cooperative randomized clinical trials, the combination of carboplatin and paclitaxel still remains
the best performing chemotherapy regimen. Yet, no substantial decrease has been seen in death rates, as the majority of patients
relapse and die from their disease despite response to first-line therapy (Ozols 2006). Thus novel therapeutic approaches
are direly needed. Although traditionally considered unresponsive to immune therapy, increasing evidence indicates that ovarian
cancers are, in fact, immunogenic tumors. This evidence comes from diverse epidemiologic and clinical data comprising evidence
of spontaneous antitumor immune response and its association with longer survival in a proportion of ovarian cancer patients;
evidence of tumor immune evasion mechanisms and their association with short survival in some ovarian cancer patients; and
finally pilot data supporting the efficacy of immune therapy.
12/2010: pages 211-228;
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ABSTRACT: In the past decade, we have witnessed important gains in the treatment of ovarian cancer; however, additional advances are required to reduce mortality. With compelling evidence that ovarian cancers are immunogenic tumors, immunotherapy should be further pursued and optimized. The dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory antibodies, create new opportunities in ovarian cancer therapeutics. Herein, we review current progress and future prospects in vaccine and adoptive T-cell therapy development as well as immunomodulatory therapy tools available for immediate clinical testing.
Journal of Clinical Oncology 11/2010; 29(7):925-33. · 18.37 Impact Factor
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ABSTRACT: In the past decade we have witnessed important advances in the treatment of gynecological cancers and have recognized their potential immunogenicity. This has opened the door to explore immune therapy not only in HPV-induced cancers but also in ovarian and endometrial cancers. Here we will review the off-target immune effects of select chemotherapy drugs commonly used to treat gynecologic cancers and novel tools that can stimulate both the adaptive and innate immune mechanisms such as novel pleiotropic cytokines, Toll-like receptors, and powerful antibodies that can target inhibitory checkpoints, thereby activating effector cellular immune mechanisms and neutralizing suppressor cells. We will also review how existing drugs can be used for combinatorial tumor therapy.
Gynecologic Oncology 12/2009; 116(2):222-33. · 3.89 Impact Factor
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ABSTRACT: The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ET(A)R). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ET(A)R. In this review, we discuss a novel role of the endothelin-B-receptor (ET(B)R) in tumorigenesis and the effect of its blockade during cancer immune therapy. We highlight key characteristics of the B receptor such as its specific overexpression in the tumor compartment; and specifically, in the tumor endothelium, where its activation by ET-1 suppresses T-cell adhesion and homing to tumors. We also review our recent findings on the effects of ET(B)R-specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy.
Clinical Cancer Research 07/2009; 15(14):4521-8. · 7.74 Impact Factor
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ABSTRACT: Whole tumor cell lysates can serve as excellent multivalent vaccines for priming tumor-specific CD8(+) and CD4(+) T cells. Whole cell vaccines can be prepared with hypochlorous acid oxidation, UVB-irradiation and repeat cycles of freeze and thaw. One major obstacle to successful immunotherapy is breaking self-tolerance to tumor antigens. Clinically approved adjuvants, including Montanide™ ISA-51 and 720, and keyhole-limpet proteins can be used to enhance tumor cell immunogenicity by stimulating both humoral and cellular anti-tumor responses. Other potential adjuvants, such as Toll-like receptor agonists (e.g., CpG, MPLA and PolyI:C), and cytokines (e.g., granulocyte-macrophage colony stimulating factor), have also been investigated.
International Reviews Of Immunology 30(2-3):150-82. · 3.43 Impact Factor
