Noweeda Mirza

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.

Vascular Endothelial Growth Factor-Trap Overcomes Defects in Dendritic Cell Differentiation but Does Not Improve Antigen-Specific Immune Responses

Purpose: Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis. Experimental Design: Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment. Results: VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC. Conclusions: Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.

Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth

Identification of a population of Foxp3-expressing suppressive macrophages.

Comment on "Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells".

In a recent article, Kryczek et al. ([1][1]) demonstrated that CD4+CD25+ regulatory T cells (Tregs) rendered monocytes immunosuppressive via up-regulation of B7-H4. We were particularly interested in the reported fact that Tregs were required for conditioning of human monocytes to exert suppressive

Targeting Toll-Like Receptor for the Induction of Immune and Antitumor Responses

A very unique and important feature of TLR (toll-like receptor) agonists is their ability to modulate TLR on the cells of the innate immune system resulting in changes that will induce effective and efficient adaptive immune responses. Therefore, stimulation of TLR pathways through their respective ligands presents a potentially attractive approach to activate adaptive anticancer immune responses. In this chapter, we summarize the effect of targeting some of the TLR for the induction of antitumor responses. Although the use of TLR agonists as future vaccine adjuvants seems very promising, we also need to proceed with caution and long term studies will be critical in assessing the propensity of chronic therapy to trigger autoimmune conditions or promote tumor growth.

Different Approaches to Dendritic Cell-Based Cancer Immunotherapy

In this chapter, we discuss the development of cancer vaccines, using as an example a vaccine based on dendritic cells transduced with wild-type p53. We discuss requirements for tumor-associated antigens, antigen carriers, and selection of patients. Theoretical considerations are supported by specific experiments testing p53 vaccine in preclinical settings in vitro and in vivo.