Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy

Gribben, John G.; Ryan, David P.; Boyajian, Richard; Urban, Robert G.; Hedley, Mary Lynne; Beach, Kathleen J.; Nealon, Patrick; Matulonis, Ursula A.; Campos, Susana M.; Gilligan, Timothy D.; Richardson, Paul G.; Marshall, Blossom; Neuberg, Donna; Nadler, Lee M.

doi:10.1158/1078-0432.ccr-04-2111

Cited by 150 publications

(95 citation statements)

References 17 publications

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“…Most of the 17 vaccinated patients progressed, and all but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted >1 year (41). In another recent phase I study, similar results were obtained in patients with glioma (42).…”

Section: Discussionmentioning

confidence: 55%

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Antonia

Mirza

Fricke

et al. 2006

Clinical Cancer Research

391

272

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Purpose: The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer. Experimental Design: Twenty-nine patients with extensive stage small cell lung cancer were vaccinated repeatedly at 2-week intervals. Most of the patients received three immunizations. p53-specific responses were evaluated, and phenotype and function of Tcells, DCs, and immature myeloid cells were analyzed and correlated with antigen-specific immune responses. Objective clinical response to vaccination as well as subsequent chemotherapy was evaluated.Results: p53-specificTcell responses to vaccination were observed in 57.1% of patients. Immunologic responses to vaccination were positively associated with a moderate increase in the titer of antiadenovirus antibodies, and negatively with an accumulation of immature myeloid cells. One patient showed a clinical response to vaccination whereas most of the patients had disease progression. However, we observed a high rate of objective clinical responses to chemotherapy (61.9%) that immediately followed vaccination. Clinical response to subsequent chemotherapy was closely associated with induction of immunologic response to vaccination. Conclusions: This study provides clinical support for an emerging paradigm in cancer immunotherapy, wherein optimal use of vaccination might be more effective, not as a separate modality, but in direct combination with chemotherapy.

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Section: Discussionmentioning

confidence: 55%

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Antonia

Mirza

Fricke

et al. 2006

Clinical Cancer Research

391

272

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“…On the other hand, CYP1B1 mRNA and protein expression has been found in a wide range of malignant tumours and in metastatic disease (McFadyen et al, 2001a), but the CYP1B1 protein is generally not detected in normal tissue at important levels (Gibson et al, 2003). Taking advantage of this, several agents activated by CYP1B1 are currently in preclinical evaluation, such as resveratrol and phortress (Potter et al, 2002;Leong et al, 2003); in addition, there is a CYP1B1 vaccine (Zyc300) in phase I/II trials, aimed to destroy cancer cells through induction of T-cell response (Gribben et al, 2005). Similar strategies could be initiated with other P450s mainly identified in tumour cells, such as CYP2W1, CYP2J2 and CYP4Z1, after identification of an appropriate prodrug.…”

Section: P450 As a Drug Target In Cancer Therapymentioning

confidence: 99%

Cytochrome P450 pharmacogenetics and cancer

2006

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The cytochromes P450 (CYPs) are key enzymes in cancer formation and cancer treatment. They mediate the metabolic activation of numerous precarcinogens and participate in the inactivation and activation of anticancer drugs. Since all CYPs that metabolize xenobiotics are polymorphic, much emphasis has been put on the investigation of a relationship between the distribution of specific variant CYP alleles and risk for different types of cancer, but a consistent view does not yet exist. This is to a great extent explained by the fact that the CYPs involved in activation of precarcinogens are in general not functionally polymorphic. This is in contrast to CYPs that are active in drug biotransformation where large interindividual differences in the capacity to metabolize therapeutic drugs are seen as a consequence of polymorphic alleles with altered function. This includes also some anticancer drugs like tamoxifen and cyclophosphamide metabolized by CYP2D6, CYP2C19 and CYP2B6. Some P450 forms are also selectively expressed in tumours, and this could provide a mechanism for drug resistance, but also future therapies using these enzymes as drug targets can be envisioned. This review gives an upto-date description of our current knowledge in these areas.

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“…In another phase 1 study, 11 patients with different types of advanced cancer were immunized with the antigen cytochrome P450 1B1 (CYP1B1), which is overexpressed on almost all human tumors. 12 About 30% of patients in that study developed immunity to CYP1B1, and half of those patients developed disease stabilization.…”

Section: Therapeutic Vaccines Combined With Chemotherapymentioning

confidence: 99%

A new era in anticancer peptide vaccines

Perez

Hofe

Kallinteris

et al. 2010

Cancer

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The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides.

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Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy

Cited by 150 publications

References 17 publications

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Cytochrome P450 pharmacogenetics and cancer

A new era in anticancer peptide vaccines

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