New Generation Vaccine Induces Effective Melanoma-Specific CD8+ T Cells in the Circulation but Not in the Tumor Site

Abstract

Although increasing evidence suggests that CTL are important to fight the development of some cancers, the frequency of detectable tumor-specific T cells is low in cancer patients, and these cells have generally poor functional capacities, compared with virus-specific CD8+ T cells. The generation with a vaccine of potent CTL responses against tumor Ags therefore remains a major challenge. In the present study, ex vivo analyses of Melan-A-specific CD8+ T cells following vaccination with Melan-A peptide and CpG oligodeoxynucleotides revealed the successful induction in the circulation of effective melanoma-specific T cells, i.e., with phenotypic and functional characteristics similar to those of CTL specific for immunodominant viral Ags. Nonetheless, the eventual impact on tumor development in vaccinated melanoma donors remained limited. The comprehensive study of vaccinated patient metastasis shows that vaccine-driven tumor-infiltrating lymphocytes, although activated, still differed in functional capacities compared with blood counterparts. This coincided with a significant increase of FoxP3+ regulatory T cell activity within the tumor. The consistent induction of effective tumor-specific CD8+ T cells in the circulation with a vaccine represents a major achievement; however, clinical benefit may not be achieved unless the tumor environment can be altered to enable CD8+ T cell efficacy.

Vaccination‐induced functional competence of circulating human tumor‐specific CD8 T‐cells

“…The present data are in agreement with our previous report 17 that vaccination with peptide, CpG and IFA induced higher CD8 T-cell numbers and more pronounced effector differentiation than vaccination with DNA, recombinant viral vectors, or peptides and proteins in vaccine formulations without CpG. 22 Following multiple booster vaccinations, T-cell responses were maintained at high levels over extended periods of time, confirming previous data on cancer-specific human CD8 Tcells. 35,36 The functionality on a per T-cell basis was increased in patients with high T-cell frequencies, as observed previously in mice and humans.…”

“…3b) which is characteristic for advanced differentiation of virus-specific CD8 T-cells. 22 This is not usually observed after T-cell vaccination, except after vaccination with peptide and CpG. When comparing patients with strong T-cell responses (>0.5% of tumor-specific cells) with those with weaker T-cell responses, we found that the former contained significantly higher proportions of CD28 neg cells (Fig.…”

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

“…As a result a potent, cell-mediated T H 1 response is initiated. A humoral immune response is also initiated as TLR9 agonists enhance differentiation of B cells into antibody-secreting plasma cells, potentially promoting antibody-dependent cellular cytotoxicity (Appay et al, 2006). An understanding of the immune cascade initiated by TLR9 activation has prompted the clinical development of several TLR9 agonists in the fields of infectious disease, cancer and asthma/allergy.…”

“…These CpG ODN adjuvants have been heavily studied for the treatment of infectious diseases, and several clinical trials are also investigating their activity as tumor vaccines. The addition of CPG 7909 to a peptide MART-1 vaccine in patients with human leukocyte antigen-A2 þ melanoma caused an approximate 10-fold increase in the number of antigen-specific CD8 þ T cells (Speiser et al, 2005;Appay et al, 2006). Anti-MAGE-3 antibody titers were enhanced with the addition of CPG 7909 to a MAGE-3 recombinant protein vaccine in a phase I/II trial, and one patient had a durable objective response (PR for 9 þ months) (van Ojik et al, 2002).…”

Mechanisms of local immunosuppression in cutaneous melanoma

“…As yet no truly successful anti-melanoma vaccine has been developed, although various strategies have been tested. In general, numerous tumour-reactive T lymphocytes can be detected in the patient's blood following vaccination, but tumour growth is unaffected (Arienti et al, 1996;Lee et al, 1998;Baurain et al, 2000;Appay et al, 2006). One explanation is that the tumour microenvironment is so immunosuppressive that any incoming effector cell is impeded (Appay et al, 2006).…”