U19 CA 113341
Combinational Immunotherapies to Amplify Vaccine Induce*
Combinational Immunotherapies to Amplify Vaccine Induce*
| September 26, 2005 - April 30, 2010 | |
| PRINCIPAL INVESTIGATOR |
Elizabeth Jaffee, M.D., Ph.D.
Johns Hopkins University Dept. of Oncology 1650 Orleans Street, CRB 4M07 Baltimore, MD 21231 |
| ABSTRACT | |
| (Description provided by applicant) | |
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T cells represent critical immunologic effectors in the anti-tumor immune response
produced by therapeutic cancer vaccines. The investigators participating in this NCDDG
grant have all been involved in utilizing current molecular technology to develop novel
approaches for inducing T cell-mediated anti-tumor immune responses. In addition, they
recently identified a new candidate tumor antigen that is overexpressed by the majority
of pancreatic and ovarian cancers. Mesothelin is one of a large category of identified
tumor-associated, non-mutated self-antigens which is overexpressed by tumor cells relative
to normal tissue. Although there are examples of the induction of T cell responses against
this category of antigens, including mesothelin, currently employed vaccine approaches are
not potent enough to overcome the mechanisms of peripheral tolerance that occur to these
self-antigens. Therefore, it is necessary to utilize relevant animal models for identifying
the most potent combinatorial vaccine approaches that can overcome natural mechanisms of
peripheral tolerance, systemic and locally within the tumor's micro-environment, and thus be
worthy of clinical testing. Drs. Jaffee and Wu are developing the reagents and testing
mesothelin-targeted vaccine approaches, in two mesothelin-expressing, murine tumor models, a
pancreatic and ovarian tumor model, respectively. Taking advantage of active scientific
collaborations with Drs. Pardoll and Chen, which have been ongoing over the past 10 years,
the NCDDG group now proposes to utilize these two mouse models to evaluate and develop more
potent antigen-specific vaccine strategies combined with immune modulators in the form of
biologics, that can overcome tolerance to tumor-associated self antigens. This development
will follow a four step process: 1) Individual vaccine strategies under development by the
NCDDG project leaders will be optimized for a number of parameters using transplantable
pancreas and ovarian tumors. Each model provides unique opportunities to understand local
T cell tolerance in the tumor's micro-environment. 2) Baseline immunologic effector functions
will be measured as an additional parameter for identifying the most potent vaccine approaches.
3) Optimized vaccine approaches will then be compared head-to-head for the ability to
eradicate naturally developing hepatic metastases (pancreatic tumor model) and peritoneal
metastases (ovarian tumor model). 4) Based on data from the in vivo studies and the measured
immune parameters, a targeted evaluation of potential synergies between different vaccine
strategies will be evaluated using potency against hepatic pancreatic tumor metastases and
peritoneal ovarian tumor metastases as the final outcome.
PROGRAMS:
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