Kerstin Menander

Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer

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 T cells, 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-specific T cell 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.

p53 therapy in a patient with Li-Fraumeni syndrome

Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patients tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy. [Mol Cancer Ther 2007;6(5):1478–1482

Cancer targeting using tumor suppressor genes

Conventional cancer treatments include cytotoxic chemotherapies and radiotherapy, which result in significant collateral toxicities. The goal for future cancer treatments is to leverage improved understanding of cancer biology mechanisms and thereby develop targeted drugs that display exquisite tumor selectivity and avoid iatrogenic damage. In this review, we discuss the potential of tumor suppressor genes for development of cancer-selective drugs using the tumor suppressor p53 as an archetype.

Tp53 gene therapy for cancer treatment and prevention

Abnormalities in the tumor suppressor TP53 are among the most common mechanisms of cancer pathogenesis (Lane and Levine 2010) and formed the rationale for TP53 gene therapy to restore normal p53 function in cancer treatment. Several important principles were elucidated in preclinical tumor models which predicted the outcomes of subsequent clinical trials including synergistic antitumor activity for combined TP53 gene therapy plus DNA damaging chemotherapy and radiation (Zhang and Roth 1994; Gjerset and Sobol 1997; Nielsen and Maneval 1998).

Antibody-mediated blockade of phosphatidylserine enhances the anti-tumor activity of targeted therapy and immune checkpoint inhibitors by affecting myeloid and lymphocyte populations in the tumor microenvironment

The underlying cause for the failure of immune checkpoint blockade is the overwhelming, persistent and multifocal immune suppression in the tumor microenvironment. This is due to the absence of pre-existing antitumor Teff because of the action of important upstream immune checkpoints that recruit immunosuppressive cytokines (e.g., TGF-beta and IL-10) and tumor infiltrating myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2 macrophages that can occupy up to 50% of the tumor mass. The membrane phospholipid, phosphatidylserine (PS), is an upstream immune checkpoint. In normal non-tumorigenic cells, PS is segregated to the inner leaflet of the plasma membrane but becomes externalized to the outer leaflet of the plasma membrane in cells in the tumor microenvironment. PS is recognized and bound by PS receptors on immune cells where it induces and maintains immune suppression. PS-targeting agents block PS-mediated immunosuppression by multifocal reprograming of the immune cells in the tumor microenvironment to support immune activation. Antibody-mediated PS blockade reduces the levels of MDSC, TGF-beta, and IL-10 and increases the levels of TNF-alpha and IL-12. PS blockade also re-polarizes tumor-associated macrophages (TAMs) from predominant M2 to predominant M1 phenotype, promotes the maturation of dendritic cells (DCs) and induces potent adaptive antitumor T cell immunity. In a Phase II clinical study, immunohistochemical evaluation of HCC tumor tissues post combination treatment indicated an increase of immune infiltrates; raising the potential of a clinically meaningful anti-tumor immune response. Pre-clinically, we demonstrate that PS targeting agents enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies in immunocompetent models of melanoma (B16 and K1735) and breast (EMT-6) cancer and that tumor growth inhibition correlates with an increase in the infiltration of activated T cells and myeloid cells and the induction of adaptive immunity. In summary, PS blockade in combination with targeted therapy and other immune checkpoint inhibitors promotes a robust, localized, anti-tumor response and represents a promising strategy to enhance cancer immunotherapy.

Correlative studies of a Phase II clinical study of bavituximab and sorafenib in patients with advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer worldwide. The incidence and mortality of HCC have increased three-fold in the United States over the past few years and the majority of patients present with advanced disease. Bavituximab is a novel chimeric IgG1 monoclonal antibody that selectively blocks phosphatidylserine (PS), a membrane phospholipid exposed on the tumor vasculature, tumor cells and tumor-derived exosomes. PS is tightly segregated to the inner leaflet of the plasma membrane, but becomes externalized on the outer surface of dying cells and vascular endothelium in response to oxidative stress, hypoxia, chemotherapy, radiation and other physiological stressors in the tumor microenvironment. Pre-clinical data demonstrate that Sorafenib increases PS exposure on vascular endothelium and HCC tumor cells. The combination of Sorafenib with a murine Bavituximab analogue potentially inhibited HCC tumor xenograft growth and induced an immunostimulatory macrophage phenotype. Following the preclinical efforts, a Phase I study was completed concluding that Sorafenib (400 mg) and Bavituximab (3 mg/kg) can be safely given in patients with advanced HCC.