Cytotoxic T lymphocyte response against non-immunoselected tumor antigens predicts the outcome of gene therapy with IL-12-transduced tumor cell vaccine

Abstract

The colon adenocarcinoma C26, carrying two endogenous related tumor antigens, whereas nonresponders had CTL tumor-associated antigens (TAA) recognized by CTL, has that recognized preferentially the FR␣ antigen. CD8 from been transduced with the gene coding for the human folate responder mice were characterized to release high levels receptor ␣ (FR␣) as an additional antigen in order to study of granulocyte-macrophage (GM)-CSF upon antigen the efficacy of vaccination against a tumor expressing mulstimulation. Tumors obtained from mice that died despite tiple antigens. A dicistronic vector was used to transduce vaccination lost expression of the FR␣ transgene but mainthe IL-12 genes to create C26/IL-12/FR␣ that has been tained expression of endogenous C26 antigens. Immunoused as a cellular vaccine to treat mice bearing lung metselection against FR␣ antigen was not observed in tumors astases of C26/FR␣. After vaccination mice were partially from non-vaccinated controls and from CD8-depleted vacsplenectomized and splenic lymphocytes frozen and used cinated mice. Down-regulation of FR␣ antigen expression retrospectively to study in vitro CD8 T cell response related was due, at least in part, to methylation of retroviral vector to the treatment outcome. Vaccination cured 50% of mice long terminal repeat promoter since FR␣ expression was and the effect was CD8 T cell dependent. Mice either cured partially restored, ex vivo, by treatment with 5-aza-2Ј-(responders) or not cured (nonresponders) by vaccination deoxy-cytidine (aza). These results indicate that CD8 T developed tumor-specific CTL. However, analysis of CTL cell-mediated immunoselection and production of GM-CSF specificity and pCTL frequencies revealed that responders are determining factors for the efficacy of tumor vaccines. had a predominant CTL activity against endogenous C26-

Intratumoral immunotherapy: using the tumour against itself

“… 141 In this model, administration of a liver pathogen was required to initiate T‐cell‐mediated autoimmune liver destruction 141 . Similarly, multiple strategies have been demonstrated to generate measurable cytotoxic T‐lymphocyte (CTL) responses in patients, without significant correlation to clinical responses 142–144 . The presence of large numbers of transgenic or in vitro ‐expanded tumour antigen‐specific T cells does not consistently cause regression of tumours in animals or patients 145–147 …”

Mature Dendritic Cells Prime Functionally Superior Melan-A-Specific CD8+ Lymphocytes as Compared with Nonprofessional APC

“…To improve cytolytic activity and IFN-␥ production of tumorprimed CTL, one could envision inclusion of immunostimulatory cytokines in the priming phase (42,43). However, in preliminary experiments, addition of exogenous IL-12 to allogeneic cells resulted in a dramatic inhibition of the expansion of melan-A tetramer ϩ CTL (M. Salio, unpublished results).…”

A Neoadjuvant/Adjuvant Randomized Trial of Colorectal Cancer Patients Vaccinated with an Anti-Idiotypic Antibody, 105AD7, Mimicking CD55

“…GM-CSF is vital for antigen presentation (31,32) and has successfully been used as an adjuvant in colorectal cancer vaccine trials (20,21). Vaccination of mice with a tumor cell vaccine indicated that GM-CSF production is a determining factor for treatment efficacy (26).…”

“…The concordance for GM-CSF and TNF-a anti-CD55 responses was 9 of 13 (71%). TNF-a and GM-CSF are known to have potent antitumoral effects (25,26). TNF-a induces apoptosis in cancer cells (25).…”