Randomized Phase I/II Evaluation of Neoadjuvant Administration of a Chemokine-Modulatory Regimen in Patients With Recurrent Resectable Colorectal Cancer
A previously-demonstrated correlation between the density of CRC-infiltrating effector T
cells and long-term outcomes (Galon et al., 2006; Pages et al., 2005) has been established.
In preclinical ex vivo studies performed using explants of resected metastatic CRC, the
combination of IFNα with nonselective or COX2-selective inhibitors of prostaglandin
synthesis resulted in elevated production of the effector T cell-attracting chemokines
CXCL10 and CCL5. This was associated with concomitant suppression of the intratumoral
expression of CCL22, a Treg-attracting chemokine (Muthuswamy et al 2008 Canc Res, and
Muthuswamy et al, submitted to Canc Res 2011). However, in a subset of patients, the optimal
results, particularly with regard to CCL5 induction, required additional stimulation by a
third agent, poly-I:C (a toll-like receptor -TLR Ligand).
Therefore, the investigators seek to establish the safety profile of a novel chemokine
regimen consisting of IFN, celecoxib and poly-I:C. The investigators also hypothesize that
the proposed neoadjuvant chemokine modulation treatment in recurrent CRC patients undergoing
tumor resection may increase the density of tumor infiltrating lymphocytes (TILS).
In addition, treatment in the neoadjuvant setting will allow a comparative analysis of the
effect of chemokine modulation on the local recruitment of effector-type T cells and the
de-recruitment of Treg within resected tumor tissues; helping to determine the "preferred"
chemokine-modulating regimen for subsequent extended studies. Such prospective studies will
focus on using combinations of chemokine modulation and cancer vaccines in patients with
CRC. The investigators have, for example, recently observed that αDC1, a new type of DC
vaccine (Kalinski and Okada, 2010; Mailliard et al., 2004) is particularly effective in
inducing the effector pathway of T cells differentiation. This was manifested by the
induction of tumor-killing function and the induction of effector-type chemokine receptors
(CXCR3 and CCR5) (Kalinski and Okada, 2010; Watchmaker et al., 2010). Combining the
αDC1vaccine to a safe, tolerable and efficacious CKM regimen may hold promise for patients
with poor prognostic CRC.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary - safety
Safety: This will be assessed by adaptive evaluation of RLTs associated with each dose and selecting a dose with a maximum 33% RLT rate. Further continuous monitoring of safety will occur during the efficacy phase.
Amer H Zureikat, MD
University of Pittsburgh
United States: Food and Drug Administration
|UPMC Hillman Cancer Center||Pittsburgh, Pennsylvania 15232|