Vaccination With a Recombinant Protein Encoding the Tumor-specific Antigen NY-ESO-1 Elicits an A2/157-165-specific CTL Repertoire Structurally Distinct and of Reduced Tumor Reactivity Than That Elicited by Spontaneous Immune Responses to NY-ESO-1-expressing Tumors

In a recent vaccination trial assessing the immuno-genecity of an NY-ESO-1 (ESO) recombinant protein administered with Montanide and CpG, we have obtained evidence that this vaccine induces specific cytolytic T lymphocytes (CTL) in half of the patients. Most vaccine-induced CTLs were directed against epitopes located in the central part of the protein, between amino acids 81 and 110. This immunodominant region, however, is distinct from another ESO CTL region, 157-165, that is a frequent target Of Spontaneous CTL responses in A2(+) patients bearing ESO+ tumors. In this study, we have investigated the CTL responses to ESO 157-165 in A2(+) patients vaccinated with the recombinant protein. Our data indicate that after vaccination with the protein, CTL responses to ESO 157-165 are induced in some, but not all, A2(+) patients. ESO 157-165-specific CTLs induced by vaccination with the ESO protein were functionally heterogeneous in terms Of tumor recognition and often displayed decreased turner reactivity as compared with ESO 157-165-specific CTLs isolated from patients with spontaneous immune responses to ESO. Remarkably, protein-induced CTLS used T-cell receptors similar to those previously isolated from patients vaccinated with synthetic ESO peptides (V beta 4.1) and distinct from those used by highly tumor-reactive CTLs isolated from patients with spontaneous immune responses (V beta 1.1, V beta 8.1, and V beta 13.1). Together, these results demonstrate that vaccination with the ESO protein elicits a repertoire of ESO 157-165-specific CTLs bearing T-cell receptors that are structurally distinct from those of CTLs found in spontaneous immune responses to the antigen and that are heterogeneous in term of tumor reactivity, being often poorly tumor reactive.