Systemic inflammatory status predict the outcome of k-RAS WT metastatic colorectal cancer patients receiving the thymidylate synthase poly-epitope-peptide anticancer vaccine.

Pierpaolo Correale,Stefano Lazzi,Maria Grazia Cusi,Cristina Ulivieri,Nicoletta Staropoli,Rocco Giannicola,Pierosandro Tagliaferri,Michele Caraglia,Luigi Pirtoli,Pierfrancesco Tassone,Domenico Ciliberto,Valerio Nardone,Pierpaolo Pastina,Cirino Botta,Silvia Zappavigna,Tatiana Cosima Baldari,Claudia Gandolfo,Antonella Fioravanti,Antonio Giordano

doi:10.18632/oncotarget.24993

Abstract

TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56dimCD16brightNKs (p < 0.04). A subset of 19 patients with activating k-ras mutations showed a different immune-inflammatory response to TSPP as compared to patients with k-ras/wt and a worse outcome in term of PFS (p = 0.048). In patients with k-ras/mut, inflammatory markers lost their predictive value and their survival directly correlated with the baseline levels of IL17/A over the median value (p = 0.01). These results provide strong hints for the design of further clinical trials aimed to test TSPP vaccination in mCRC patients.

Highlights

Thymidylate-synthase poly-epitope peptide (TSPP) is a 27-mer vaccine construct which contains the amino-acidic sequences of three known cytotoxicT-lymphocyte (CTL) epitopes with HLA-A(*)02.01 amino-acid anchorage motifs (TS-1, TS-2, and TS-3) derived from the thymidylate synthase (TS) and showing promising antitumor activity in preclinical models [1,2,3,4]
The trial investigated the effects of TSPP vaccination alone or associated with granulocyte macrophagecolony-stimulating-factor (GM-CSF) and interleukin-2 (IL-2) [5, 7], or in concomitant (Arm-C/DL1-3) or sequential combination with a previously characterized [5, 6] chemo-immunotherapy regimen with gemcitabine, oxaliplatin, levo-folinic acid (FA) and bolus/ infusional 5-FU followed by IL-2 and GM-CSF (GOLFIG regimen) [6, 8,9,10,11]
The results of the TSPP/VAC 1 trial suggested that TSPP vaccination is safe, induces immune-modulatory effects and exerts antitumor activity in 41pretreated metastatic colorectal cancer (mCRC) patients, who showed a Progression-free survival (PFS) and Overall survival (OS) of 6.9 and 14.9 months, respectively

Summary

INTRODUCTION

Thymidylate-synthase poly-epitope peptide (TSPP) is a 27-mer vaccine construct which contains the amino-acidic sequences of three known cytotoxicT-lymphocyte (CTL) epitopes with HLA-A(*)02.01 amino-acid anchorage motifs (TS-1, TS-2, and TS-3) derived from the thymidylate synthase (TS) and showing promising antitumor activity in preclinical models [1,2,3,4]. Several studies suggest that cytotoxic drugs like oxaliplatin, gemcitabine, 5-FU or cyclophosphamide, mAbs to EGFR and VEGF, as well as radiotherapy, may induce immunogenic cell death, and shape mCRC microenvironmental conditions making the residual tumor tissue more sensitive to activated immune-effectors. On these bases, our group investigated the antitumor activity and the toxicity of the TSPP vaccination alone and in combination with 5-FU in HLA-A(*)02.01 (HHD) transgenic mice inoculated subcutaneously with TS-expressing EL-4/ HHD lymphoma cells. We attempted to identify potential biomarkers predictive of treatment response to TSPP by carrying -out a retrospective analysis on a cohort of 41 mCRC patients enrolled in the TSPP/VAC1 trial

RESULTS

DISCUSSION

Ethical considerations and study design