Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen

Abstract

Melanoma patients have high frequencies of T cells directed against antigens of their tumor. The frequency of these antitumor T cells in the blood is usually well above that of the anti-vaccine T cells observed after vaccination with tumor antigens. In a patient vaccinated with a MAGE-3 antigen presented by HLA-A1, we measured the frequencies of anti-vaccine and antitumor T cells in several metastases to evaluate their respective potential contribution to tumor rejection. The frequency of anti–MAGE-3.A1 T cells was 1.5 × 10−5 of CD8 T cells in an invaded lymph node, sixfold higher than in the blood. An antitumor cytotoxic T lymphocyte (CTL) recognizing a MAGE-C2 antigen showed a much higher enrichment with a frequency of ∼10%, 1,000 times higher than its blood frequency. Several other antitumor T clonotypes had frequencies >1%. Similar findings were made on a regressing cutaneous metastasis. Thus, antitumor T cells were ∼10,000 times more frequent than anti-vaccine T cells inside metastases, representing the majority of T cells present there. This suggests that the anti-vaccine CTLs are not the effectors that kill the bulk of the tumor cells, but that their interaction with the tumor generates conditions enabling the stimulation of large numbers of antitumor CTLs that proceed to destroy the tumor cells. Naive T cells appear to be stimulated in the course of this process as new antitumor clonotypes arise after vaccination.

The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy

“…However, these natural pre-vaccine immune responses are often too weak to result in tumor rejection or even a reduction in tumor growth, due to the various immune suppressive mechanisms that occur within the tumor microenvironment [34]. Vaccination can then aid in boosting these spontaneous immune responses, either by aiding to overcome tumor-induced immune suppression, by re-activating anergic tumorreactive T cells at the tumor site, or by inducing new antitumor CTL clonotypes (probably due to additional antigen release from attacked tumor cells) [3,35]. This priming of the immune system by a growing tumor could explain why the immunogenicity of the mRNA sonoporated DCs was more pronounced in a therapeutic setting.…”

Dendritic cells in cancer immunotherapy

“…The workup of the patients treated by C.W. Schmidt's group [89,90] using a laborious yet highly informative strategy [4] has shown that the vaccine-induced immune responses are dominated by highly individualized responses to shared and neoantigens generated by somatic point mutations (Thomas Wölfel, personal communication) in congruence with previous observations in select melanoma patients [3,4]. The mRNA transfection approach allows for exploring the total antigenic repertoire of tumors without limitations imposed by availability of tumor tissue, as even a few cells can provide sufficient amounts of mRNA for PCR amplification [81].…”

“…Current vaccination strategies must be improved to achieve higher T-cell frequencies and most importantly, the quality of these T cells must be comparable to the protective T-cell response observed during acute or chronic viral infections. This is expected to enhance clinical efficacy, as already small numbers of highquality vaccine T cells appear to be able to induce regressions in a minority of patients by inducing a second wave of T cells (the so-called ''spark'' hypothesis) [2,3]. In addition, somatically mutated antigens, which are associated with regression and long-term survival [3,4], should be tested, as well as antigens relevant for the oncogenic phenotype (mutated and viral oncogenes, certain non-mutated antigens that tumors overexpress) to diminish antigen loss and escape [5,6].…”

“…This is expected to enhance clinical efficacy, as already small numbers of highquality vaccine T cells appear to be able to induce regressions in a minority of patients by inducing a second wave of T cells (the so-called ''spark'' hypothesis) [2,3]. In addition, somatically mutated antigens, which are associated with regression and long-term survival [3,4], should be tested, as well as antigens relevant for the oncogenic phenotype (mutated and viral oncogenes, certain non-mutated antigens that tumors overexpress) to diminish antigen loss and escape [5,6]. Side effects observed recently with adoptive T-cell therapy [7] suggest that tumor-specific antigens (such as cancer testis or mutated antigens, or Muc-1) [5,6,8] should be prioritized to avoid similar toxicity with highly immunogenic cancer vaccines of the future.…”

Biomarkers for the Development of Cancer Vaccines

“…The presence of a specific immune response does not necessarily correlate with clinical outcome. In a recent melanoma trial using a peptide specific for an epitope in MAGE-3 presented by HLA-A1, it was found that the most important response was to a completely different peptide, derived from MAGE-C2 and presented by HLA-A2 [34,35]. Furthermore, the choice of biomarker for immunological readout is often dictated by the nature of the vaccine, rather than biologically useful clinical response.…”