Claudia Marcela Diaz, Ph.D.
Research Assistant Professor of Medicine
Description of Research
Dr. Diaz’s studies are aimed at understanding the immune responses to tumors with the long term goal of developing effective immune-based therapies for cancer. Tumor immunologists face unique challenges such as antigenic tolerance and tumor mediated immunosuppression. Adoptive cell therapy is an attractive approach to overcome some of these challenges. However, clinical trials using ACT have been rather disappointing. It has become clear that during the process of memory development, the phenotypic and functional characteristics of T cells are altered, thus a better understanding of such characteristics will allow us to identify the subpopulation of T cells best suited for ACT, and as such, to develop effective strategies to promote the development and persistence of such subtypes. Dr. Diaz’s laboratory recently reported that activation of naïve cells in the presence of IL-12 favor the generation of a cell subtype with an “early effector/central memory” phenotype that shows superior anti-tumor activity when used in ACT. Current work focuses on understanding the mechanisms behind their enhanced activity, and on the generation of preclinical data to support a phase I clinical trial. One caveat of this approach is that generation of enough numbers of tumor reactive human T cells for ACT is very difficult. One approach to overcome this is the redirection of TCR specificity through retroviral transduction. The laboratory is currently developing an approach that will utilize TCR-transduced human T cells activated in the presence of IL-12. Given the complexity of TCR transduction, which may limit its widespread clinical application, the laboratory is testing the approach of increasing the number of class I molecules presenting antigen by using an HLA-A2-IgG-Fc fusion molecule. This approach has the advantage of allowing the utilization of multiple HLA-A2 restricted peptides, decreasing the possibility of therapeutic failure due to immunoediting, as well as non-viral alternatives for the genetic modification of T cells.
Highlights
- Cytokine signaling at the time of priming impacts on the phenotypic and functional characteristics of the resulting population, and represents a viable strategy to effectively program T cells for ACT.
- CD8+ T cells bearing an “early effector-central memory” phenotype have upregulated expression of homing molecules such as CD62L and receptors for survival cytokines such as CD127, and also have superior in vivo activity after ACT.
- Enhanced anti-tumor activity in vivo of donor T cells correlates with their ability to persist after transfer.
- Long term survivor donor T cells activated in the presence of IL-12 display memory stem cell traits such as expression of Sca-1 and the capability of immune reconstitution following chemotherapy-induced lymphodepletion.
Selected Cancer-Related Publications
- Salem ML, Diaz-Montero CM, Al-Khami AA, El-Naggar SA, Naga O, Montero AJ, Khafagy A, Cole DJ. Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol 182:2030-40, 2009. Read more »
- Salem ML, Diaz-Montero CM, El-Naggar SA, Chen Y, Moussa O, Cole DJ. The TLR3 agonist poly(I:C) targets CD8+ T cells and augments their antigen-specific responses upon their adoptive transfer into naïve recipient mice. Vaccine 27(4):549-57, 2009. Read more »
- Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58(1):49-59, 2009. Read more »
- Montero AJ, Diaz-Montero CM, Millikan RE, Liu J, Do KA, Hodges S, Jonasch E, McIntyre BW, Hwu P, Tannir N. Cytokines and angiogenic factors in patients with metastatic renal cell carcinoma treated with interferon-alpha: association of pretreatment serum levels with survival. Ann Oncol 20:1682-7,2009. Read more »
Programs
Collaborating in the Multidisciplinary Research Program(s):