A Novel Dendritic Cell-Based Cancer Vaccine Produces Promising Results in a Syngenic CC-36 Murine Colon Adenocarcinoma Model

Jack, Angela; Aydin, Nebil; Montenegro, Grace; Alam, Khorshed; Wallack, Marc K.

doi:10.1016/j.jss.2006.09.024

Cited by 10 publications

(5 citation statements)

References 26 publications

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“…The reduced metastatic burden in the lungs after OVV-EGFP treatment could be accounted by a direct cytotoxic effect of the virus as well as the induction of antitumor immunity because of the ability of vaccinia virus to break CD4 + CD25 + regulatory T-cell-mediated tolerance through Toll-like receptor (TLR)-dependent and -independent pathways (24,25), and augment the efficacy of a cancer vaccine composed of dendritic cells pulsed with an IL-2 gene-encoded vaccinia virus tumor oncolysate (47). To investigate whether targeting of the tumor by OVV-EGFP was associated with the generation of antitumor immunity, sera were collected from the same mice that had been examined for the lung metastases at several time-points, including before tumor challenge, at the time of orthotopic 4T1 inoculation, at the time of therapy, and every 10 d until killing (Fig.…”

Section: Reduction In Metastatic Disease Following Ovv-cxcr4-a-mfc Trmentioning

confidence: 99%

Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases

Gil¹,

Seshadri

Komorowski³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

132

128

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Oncolytic viruses hold promise for the treatment of cancer, but their interaction with the tumor microenvironment needs to be elucidated for optimal tumor cell killing. Because the CXCR4 receptor for the stromal cell-derived factor-1 (SDF-1/CXCL12) chemokine is one of the key stimuli involved in signaling interactions between tumor cells and their stromal microenvironment, we used oncolytic virotherapy with a CXCR4 antagonist to target the CXCL12/CXCR4 signaling axis in a triple-negative 4T1 breast carcinoma in syngeneic mice. We show here that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intravenously to mice with orthotopic tumors attains higher intratumoral concentration than its soluble counterpart and exhibits increased efficacy over that mediated by oncolysis alone. A systemic delivery of the armed virus after resection of the primary tumor was efficacious in inhibiting the development of spontaneous metastasis and increased overall tumor-free survival. Inhibition of tumor growth with the armed virus was associated with destruction of tumor vasculature, reductions in expression of CXCL12 and VEGF, and decrease in intratumoral numbers of bone marrow-derived endothelial and myeloid cells. These changes led to induction of antitumor antibody responses and resistance to tumor rechallenge. Engineering an oncolytic virus armed with a CXCR4 antagonist represents an innovative strategy that targets multiple elements within the tumor microenvironment. As such, this approach could have a significant therapeutic impact against primary and metastatic breast cancer. viral oncotherapy | vascular targeting

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Section: Reduction In Metastatic Disease Following Ovv-cxcr4-a-mfc Trmentioning

confidence: 99%

Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases

Gil¹,

Seshadri

Komorowski³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

132

128

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“…The use of vaccinia based multivalent tumor antigen retrieval system has been tried in a compassionate clinical trial with encouraging results. In this trial, we established the premise that dendritic cells pulsed with recombinant IL-2 gene encoded vaccinia virus infected melanoma oncolysates, derived from five primary melanoma cell lines, present the MAAs present in the oncolysate to the CTLs [29,30]. This vaccine (DC-MelVac) has now been approved by the FDA for a phase 1 clinical trial.…”

Section: Discussionmentioning

confidence: 99%

Cancer Vaccines: Bench to Bedside

Tuli

Maniyar

Bednarczyk

et al. 2016

IJTS

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The immune system has immense potential in cancer therapy as it is individualized, precision driven and robust, however, it is associated with challenges of its own that include immune evasion, development of tolerance and a sustained tumor rejection response. Recent FDA approval of several checkpoint inhibitors, anti-CTLA4, anti-PD-1, has re-invigorated cancer immunology by demonstrating that tolerance to cancer can be broken to induce a sustained immune response in patients. Active immunization with multivalent tumor associated antigens (TAA), however, is still a challenge. We have developed two specific distinct methods to generate multivalent antigens capable of tumor regression in prostate cancer and melanoma. In prostate cancer, we have generated specific multivalent peptide mimetics using phage display synthetic peptide libraries capable of metastatic tumor regression in an animal model. In melanoma, we have used a vaccinia virus based antigen retrieval technology to generate a multivalent antigenic vaccine. The antigenic repertoire is well defined. A protocol for the melanoma vaccine is FDA approved for clinical Science, Vol. 2016, 33-60. doi: 10.13052/ijts2246-8765.2016.003 c 2016 34 N. Tuli et al. trials. We envision defining the humoral and cellular immune response to combine our active vaccine strategy with other treatment modalities including approved checkpoint inhibitors anti-CTLA4 and anti-PD-1. We believe our vaccine candidates are a new generation of immune-therapeutics that can prolong cancer free survival and prevent secondary recurrences. Our studies have challenged the existing paradigms to re-define cancer immunotherapy that bridges the gap between humoral and cellular immunity by combining active immune response with negative checkpoint inhibitors thus activating pre-existing dormant immune response. International Journal of Translational

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“…Over the past few years, we have designed a new vaccine incorporating the latest advances in cell and molecular biology. We have previously demonstrated the ability of dendritic cells (DCs) pulsed with an IL-2 gene-encoded vaccinia virus (VV) melanoma oncolysate (DC-IL-2VMO or DC-MelVac) to generate a cellular immune response in vitro (39) and in murine tumor models (40). This second generation melanoma vaccine possesses key immunogenic properties that may render it a potent therapeutic agent in the treatment of patients with stage III and IV melanoma and was approved by the FDA for a phase I trial in February 2005.…”

Section: Discussionmentioning

confidence: 99%

Follow-up analysis of a randomized phase III immunotherapeutic clinical trial on melanoma

Suriano

Rajoria

George

et al. 2013

Molecular and Clinical Oncology

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Development of a melanoma-specific vaccine is of clinical necessity. Therefore, a phase III, randomized, double-blind trial was performed (June 1988-June 1991) to assess the clinical effectiveness of our vaccinia melanoma oncolysate (VMO) vaccine in stage III melanoma patients. Patient data were collected from 11 institutions, as well as from the Social Security Death Index and were analyzed from April through August 2008 for disease-free interval (DFI) and overall survival (OS). The median OS for patients who were administered the VMO vaccine was 7.71 years, compared to 7.95 years for patients administered the vaccinia virus vaccine (V) (p=0.70). The median DFI for the VMO group was six years, while the median DFI for the V group has not yet been reached. This analysis demonstrated a statistically significant difference in OS in females in both groups (VMO, 79%; V, 92%), as compared to males (VMO, 57%; V, 68%) (p=0.0473). This follow-up analysis demonstrated that females had a survival advantage over males, thus warranting further investigation. This significant observation may facilitate the recruitment of patients for future clinical trials, as well as determine which patients are more likely to benefit from receiving the VMO vaccine.

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A Novel Dendritic Cell-Based Cancer Vaccine Produces Promising Results in a Syngenic CC-36 Murine Colon Adenocarcinoma Model

Cited by 10 publications

References 26 publications

Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases

Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases

Cancer Vaccines: Bench to Bedside

Follow-up analysis of a randomized phase III immunotherapeutic clinical trial on melanoma

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