PROJECT SUMMARY/ABSTRACT
Morbidity rates for invasive colorectal cancer continue to be a major public health problem in the United States.
Although targeted treatment regimens such as antibody and small molecule-based drugs exist, no current
therapy effectively protects against late-stage disease in patients. Immunotherapeutic intervention holds
enormous potential for eliciting specific immunity against tumor spread while surmounting treatment-associated
morbidities. Unfortunately, despite advancements in countering immunosuppression and triggering potent
reactivity toward self-antigens, immune-based strategies have not impacted disease progression to date. Colon
cancer tends to display a considerable degree of genomic intra-/inter-heterogeneity, limiting a given strategy’s
eligibility in patients and long-term therapeutic index. With respect to cancer immunotherapy, the eventual
outgrowth of tumor cell variants expressing altered immunophenotypes may help explain the lack of sustained
anti-tumor responses observed clinically for locally advanced and metastatic disease. An alternative and
potentially improved immunotherapeutic approach involves abrogating tumor angiogenesis by initiating T cell
destruction against the supportive vasculature. Conceptually, as tumor-derived blood vessel function is critical
to tumorigenesis, vascular immune targets would be less amenable to therapy-induced escape and cancer
relapse. The overall objectives of this proposal are to identify unique CD8+ T cell HLA-A2+ restricted stromal
targets that potentiate therapeutic protection (and maintenance of subclinical disease) against colon carcinoma
growth under first-/second-line treatment scenarios in clinically relevant pre-clinical models. Additionally, we
intend to demonstrate prevention of colon cancer recurrence following a novel synergistically timed
immunotherapeutic regimen that incorporates cytotoxicity against both vascular and cancer cells. Our central
hypothesis is that anti-stromal CD8+ T cells prevent recurrence and achieve durable cancer protection by
mitigating angiogenesis within the TME. The following specific aims will test our central hypothesis and appraise
the successful completion of the proposal’s objectives: Aim 1 – Test the hypothesis that anti-vascular CD8+ T
cell responses induce therapeutic protection against colon carcinoma; Aim 2 – Test the hypothesis that anti-
vascular immunity prevents therapy-induced escape and synergizes with a colon cancer-specific antibody drug
conjugate. Overall, our mechanistic studies will provide a clearer perspective for engaging anti-stromal CD8+ T
cells as the TME proceeds through operational phases of immunotherapy-related sensitivity, dormancy, and
escape. Our research efforts will also led to the characterization of protective stromal-associated peptide/HLA
targets and a co-applied targeting platform, which will help spearhead the development of relevant
immunotherapeutic strategies for ultimate clinical trial evaluation in patients with colon cancer. Additionally, as
the blood vessel system is conserved, our experience with these unique peptide/HLA targets will have
therapeutic implications for other vascularized solid cancers.