Antitumor immune response induced by i.t. injection of vector-activated dendritic cells and chemotherapy suppresses metastatic breast cancer

Akbulut, Hakan; Tang, Yucheng; Akbulut, K. Gonca; Maynard, Jonathan; Zhang, Lixin; Deisseroth, Albert

doi:10.1158/1535-7163.mct-06-0049

Cited by 17 publications

(24 citation statements)

References 33 publications

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“…8,9 Although the exact mechanism of the effect of dying tumor cells on the induction of an antitumor immune response is not completely understood, the immune cells attracted to the region of tumor cell death by the released tumor antigens might have a role. We have therefore tested whether it is possible to increase the level of the anti-tumor immune response induced by s.c. injection of the Ad-sig-hMUC-1/ ecdCD40L vector prime-hMUC-1/ecdCD40L protein boost VPPP vaccine, by concomitant administration of systemic chemotherapy (5-FU) or by AdCMVCDIRE-SE1A/5FC vector-targeted chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…injection of the AdCMVCDIRESE1A/5FC in mouse models based on different cancer cells. 9,27,28 The mice treated with both the hMUC-1/ecdCD40L VPPP vaccine and the AdCMVCDIRESE1A/5FC vectortargeted chemotherapy, Group E, had the smallest tumor volume and survived longer than did mice in the other groups (Po0.001). Interestingly, the hMUC-1/ecdCD40L VPPP vaccine strategy targeting MUC-1, significantly decreased the number of CD44 +…”

Section: Cd24mentioning

confidence: 99%

“…[5][6][7][8][9] The T cells from the spleen and tumordraining lymph nodes of the mice from each experimental test group were collected 7 days following injection of last treatment. Cytotoxic T cells (CD8 positive) were purified by magnetic separation using MACS CD8a-positive T Cell Isolation Kit (Miltenyi Biotec, Auburn, CA, USA).…”

Section: -33mentioning

confidence: 99%

“…[5][6][7][8][9] Briefly, 1 Â 10 6 purified spleen T-cells were added to the MMC-treated (5 mg/ml) LL2/LL1 cells grown in T-25 flask and incubated for 5 days at 371C for cell-mediated cytotoxicity tests. Following 2 days of …”

Section: Tests For the Cellular Immune Response: Elispot Assaymentioning

confidence: 99%

“…To spare the proliferating TAA-specific CD8 effector T cells from the effects of chemotherapy, we combined AdCMVCDIRESE1A/5FC vector-targeted chemotherapy (VTCT) with the TAA/ecdCD40 L VPPP vaccination. 8,9 The CD44 + CD24 À fraction of cancer cells isolated from epithelial cancers has been shown to contain low frequency cells displaying high levels of tumorigenicity, self-renewal and chemotherapy resistance. [10][11][12][13] The importance of these cells has been validated by the discovery that cancer-associated gene expression signatures displayed by these cells correlate with therapy outcome and survival in clinical trials in human subjects.…”

Section: Introductionmentioning

confidence: 99%

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Addition of adenoviral vector targeting of chemotherapy to the MUC-1/ecdCD40L VPPP vector prime protein boost vaccine prolongs survival of mice carrying growing subcutaneous deposits of Lewis lung cancer cells

et al. 2010

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We studied the effect of adding chemotherapy or vector targeted chemotherapy to the administration of an Ad-sighMUC-1/ecdCD40L adenoviral vector prime-hMUC-1/ ecdCD40L protein boost cancer vaccine (designated hMUC-1/ecdCD40L VPPP vaccine), which were administered to test mice 10 days following subcutaneous (s.c.) inoculation of 500 000 Lewis Lung Carcinoma cells, at a time when the average volume of the s.c. tumors was 50 cu mm. The survival of hMUC-1/ecdCD40L VPPP vaccine-treated mice was twice as long as untreated mice. Addition of vector-targeted chemotherapy (AdCMVCDIRESE1A/5FC) to the hMUC-1/ ecdCD40L VPPP vaccine 10 days after tumor inoculation significantly (P ¼ 0.0062) prolonged the survival of the test mice over administration of the hMUC-1/ecdCD40L VPPP vaccine alone or the control mice (Po0.00001). Interestingly, the combination of the AdCMVCDIRESE1A/5FC vector-targeted chemotherapy to the hMUC-1/ecdCD40L VPPP vaccine decreased the levels of CD44 + CD24 À cells in s.c. deposits of the human MUC-1-positive Lewis Lung Cancer cell line (LL2/ LL1hMUC-1) by 20 fold. These results suggest that the addition of vector-targeted chemotherapy to an adenoviral-based cancer vaccine is a strategy that deserves further testing.

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Section: Discussionmentioning

confidence: 99%

Section: Cd24mentioning

confidence: 99%

Section: -33mentioning

confidence: 99%

Section: Tests For the Cellular Immune Response: Elispot Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Addition of adenoviral vector targeting of chemotherapy to the MUC-1/ecdCD40L VPPP vector prime protein boost vaccine prolongs survival of mice carrying growing subcutaneous deposits of Lewis lung cancer cells

et al. 2010

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The Development of Gene Therapy: From Monogenic Recessive Disorders to Complex Diseases Such as Cancer

Gillet

Macadangdang

Fathke

et al. 2009

Gene Therapy of Cancer

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During the last 4 decades, gene therapy has moved from preclinical to clinical studies for many diseases ranging from monogenic recessive disorders such as hemophilia to more complex diseases such as cancer, cardiovascular disorders, and human immunodeficiency virus (HIV). To date, more than 1,340 gene therapy clinical trials have been completed, are ongoing, or have been approved in 28 countries, using more than 100 genes. Most of those clinical trials (66.5%) were aimed at the treatment of cancer. Early hype, failures, and tragic events have now largely been replaced by the necessary stepwise progress needed to realize clinical benefits. We now understand better the strengths and weaknesses of various gene transfer vectors; this facilitates the choice of appropriate vectors for individual diseases. Continuous advances in our understanding of tumor biology have allowed the development of elegant, more efficient, and less toxic treatment strategies. In this introductory chapter, we review the history of gene therapy since the early 1960s and present in detail two major recurring themes in gene therapy: (1) the development of vector and delivery systems and (2) the design of strategies to fight or cure particular diseases. The field of cancer gene therapy experienced an "awkward adolescence." Although this field has certainly not yet reached maturity, it still holds the potential of alleviating the suffering of many individuals with cancer.

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Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer

Zhang

Herlyn

2008

Cancer Immunol Immunother

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Successful treatment of cancer patients with a combination of monoclonal antibodies (mAb) and chemotherapeutic drugs has spawned various other forms of additional combination therapies, including vaccines or adoptive lymphocyte transfer combined with chemotherapeutics. These therapies were effective against established tumors in animal models and showed promising results in initial clinical trials in cancer patients, awaiting testing in larger randomized controlled studies. Although combination between immunotherapy and chemotherapy has long been viewed as incompatible as chemotherapy, especially in high doses meant to increase anti-tumor efficacy, has induced immunosuppression, various mechanisms may explain the reported synergistic effects of the two types of therapies. Thus direct effects of chemotherapy on tumor or host environment, such as induction of tumor cell death, elimination of regulatory T cells, and/or enhancement of tumor cell sensitivity to lysis by CTL may account for enhancement of immunotherapy by chemotherapy. Furthermore, induction of lymphopenia by chemotherapy has increased the efficacy of adoptive lymphocyte transfer in cancer patients. On the other hand, immunotherapy may directly modulate the tumor's sensitivity to chemotherapy. Thus, anti-tumor mAb can increase the sensitivity of tumor cells to chemotherapeutic drugs and patients treated first with immunotherapy followed by chemotherapy showed higher clinical response rates than patients that had received chemotherapy alone. In conclusion, combination of active specific immunotherapy or adoptive mAb or lymphocyte immunotherapy with chemotherapy has great potential for the treatment of cancer patients which needs to be confirmed in larger controlled and randomized Phase III trials.

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Antitumor immune response induced by i.t. injection of vector-activated dendritic cells and chemotherapy suppresses metastatic breast cancer

Cited by 17 publications

References 33 publications

Addition of adenoviral vector targeting of chemotherapy to the MUC-1/ecdCD40L VPPP vector prime protein boost vaccine prolongs survival of mice carrying growing subcutaneous deposits of Lewis lung cancer cells

Addition of adenoviral vector targeting of chemotherapy to the MUC-1/ecdCD40L VPPP vector prime protein boost vaccine prolongs survival of mice carrying growing subcutaneous deposits of Lewis lung cancer cells

The Development of Gene Therapy: From Monogenic Recessive Disorders to Complex Diseases Such as Cancer

Combination of active specific immunotherapy or adoptive antibody or lymphocyte immunotherapy with chemotherapy in the treatment of cancer

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