Our translational research group is dedicated to the development of innovative cancer therapeutics. As
a part of the Hollings Cancer Center Immunotherapy program, we have been actively engaged in
understanding the mechanisms involved in the in vivo recognition of tumor associated antigens in the host
environment in order to provide the scientific basis for novel clinical strategies leading to the design of more
effective adoptive immunotherapy and cancer vaccine protocols. This R01 funded project has most recently led
to the collaborative development of dendritic cell vaccines and T-cell receptor transduction of autologous T cell
protocols which are nearing clinical trials. An abstract from a recent Program Project grant submission (Project
1) is described below:

Program Project 1. The concept of antigen specific TCR transduced lymphocytes for adoptive
immunotherapy is gaining increasing support. For this to become a reality, however, the biology and in
vivo response of these cells to the host environment, including tolerance, antigen presentation, and
tumor microenvironment will have to be carefully delineated. Our translational research group recently
has developed a series of novel observations/reagents to address this issue. First, we have observed that
cyclophosphamide (CTX) preconditioning induces post-lymphopenia expansion of DC in the PBL.
Second, we have delineated that IL-12 conditioning during in vitro priming is able to promote the
acquisition of an early effector (TEA) like phenotype. Both are associated with enhanced anti-tumor
responses in vivo. Third, our program collaborator (Dr. Shikar Mehrotra) has successfully created a
TCR transgenic mouse (termed h3T) which expresses functional melanoma antigen (tyrosinase) specific
human TCR in peripheral CD8+ T cells thus providing a source of naïve endogenous T cells expressing
tyrosinase specific TCR and TCR transduced T cells of the same specificity. We hypothesize that
combining the antigen specific response of TCR transduced CD8+ T cells with an
environment which promotes DC function will result in the generation of more effective
anti-tumor immunity. Therefore, we propose the following: Specific Aim 1 will define the impact of
homeostatic proliferation and mechanisms of IL-12 conditioning on TCR transduced T cell survival and
function in a tumor bearing host. We will then assess the mechanisms by which IL-12 conditioning
impacts on TCR transduced and h3T transgenic T cell survival looking specifically at CTLA-4, PD-1
signaling. Specific Aim 2 will define the TCR transduced CD8+ T cell response to antigen presentation in
an environment which promotes DC function evaluating both the post-lymphopenia expansion of DC
environment, and also with a limited lymphopenia post CD8+ antibody depletion. PBL from the phase I
clinical trial will be used to confirm our preclinical data for both aims. Finally, Specific Aim 3 will
determine the optimal conditions required to induce a robust memory TCR transduced CD8+ T cell
response in a tumor bearing environment evaluating the mechanisms affecting in vivo TCR transduced
CD8+ T cells responses. We will then define the therapeutic efficacy of TCR transduced T-cells
adoptively transferred into a tumor bearing mouse. Understanding the mechanisms involved in the in
vivo response of TCR transduced T cells to the host enviroment will provide the scientific basis for
novel clinical strategies leading to the design of more effective adoptive immunotherapy protocols.
Given the clinical expertise and volume of pancreatic cancer patients taken care of by our group, a more recent
second focus of our translational research group has been dedicated to the development of innovative
pancreatic cancer (PC) therapeutics. Our earlier studies have identified a novel PC related oncogene (cancerassociated Sm-like oncogene or CaSm). We have additionally shown that downregulation of CaSm with an
adenovirus expressing CaSm antisense RNA (Ad-αhCaSm) significantly reduced in vivo tumor growth with
prolonged survivorship indicating that the CaSm oncogenes could be targeted for therapeutic intervention in
PC. Based on these novel observations, we are actively working with collaborators to develop an innovative
phase I clinical trial in pancreatic cancer. An abstract from the second R01 grant (Project 2) is described below:

Project 2. We have identified and characterized a novel PC related oncogene (the Cancer-associated
Sm-like oncogene(CaSm)) and shown that: 1) it contributes to the transformed state in human and
murine PC cells, and 2) adenovirus expressing CaSm antisense RNA (Ad-alphahCaSm) significantly
reduces in vitro and in vivo tumor growth with prolonged survivorship via cyclin B1/CDK1 dependent
cytostatic cell cycle inhibition. These results indicate that the CaSm oncogene is critical to PC cell cycle
control and could be targeted for therapeutic intervention. One of the major barriers to an effective
CaSm-based gene therapy approach is achieving adequate in vivo tumor delivery. In fact, insufficient
and/or non-effective delivery of gene vectors is a global problem limiting cancer gene therapy. We have
recently established an exciting collaboration with Dr. Jesse Au's laboratory (Ohio State) that has
developed a novel pacitaxel tumor priming approach capable of enhancing the delivery large molecules
throughout an intraperitoneal tumor. Furthermore, we now have preliminary studies suggesting that
the down-regulation of CaSm may induce a bystander effect in vivo- which could alleviate the need for
delivery of the CaSm antisense gene to 100 percent of PC cells in vivo. Utilizing the downregulation of
CaSm as a novel therapeutic intervention and our recently characterized murine CaSm PC model, our
specific aims are to: 1) Determine whether paclitaxel tumor priming improves delivery and efficacy for
pancreatic cancer gene therapy, 2) Define the impact of tumor priming on, and the mechanisms by
which, the reduction of CaSm over-expression mediates a bystander effect, and 3) Define the
mechanism by which CaSm upregulation leads to PC oncogenesis. The focus of this proposal is to
combine a novel tumor priming approach with a promising gene target in order to develop innovative
PC therapeutics. Successful completion of the proposed studies will advance the research in treatment
of pancreatic cancer and, on a broader scope, validate an innovative technology for delivering gene
vectors or other nanoparticles to intraperitoneal tumors.