High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens

Abstract

After vaccination of melanoma patients with MAGE antigens, we observed that even in the few patients showing tumor regression, the frequency of anti-vaccine T cells in the blood was often either undetectable or <10−5 of CD8 T cells. This frequency being arguably too low for these cells to be sole effectors of rejection, we reexamined the contribution of T cells recognizing other tumor antigens. The presence of such antitumor T cells in melanoma patients has been widely reported. To begin assessing their contribution to vaccine-induced rejection, we evaluated their blood frequency in five vaccinated patients. The antitumor cytotoxic T lymphocyte (CTL) precursors ranged from 10−4 to 3 × 10−3, which is 10–10,000 times higher than the anti-vaccine CTL in the same patient. High frequencies were also observed before vaccination. In a patient showing nearly complete regression after vaccination with a MAGE-3 antigen, we observed a remarkably focused antitumoral response. A majority of CTL precursors (CTLp's) recognized antigens encoded by MAGE-C2, another cancer-germline gene. Others recognized gp100 antigens. CTLp's recognizing MAGE-C2 and gp100 antigens were already present before vaccination, but new clonotypes appeared afterwards. These results suggest that a spontaneous antitumor T cell response, which has become ineffective, can be reawakened by vaccination and contribute to tumor rejection. This notion is reinforced by the frequencies of anti-vaccine and antitumor CTLs observed inside metastases, as presented by Lurquin et al. (Lurquin, C., B. Lethé, V. Corbière, I. Théate, N. van Baren, P.G. Coulie, and T. Boon. 2004. J. Exp. Med. 201:249–257).

Vaccination of a Melanoma Patient with Mature Dendritic Cells Pulsed with MAGE-3 Peptides Triggers the Activity of Nonvaccine Anti-Tumor Cells

“…In the course of these studies, we also evaluated the total number of T cells present in the blood that were capable of being stimulated by autologous tumor cells and lysing these tumor cells. Such "anti-tumor" T cells were present in all metastatic melanoma patients at frequencies of ϳ10 Ϫ3 , well above the frequencies of the anti-vaccine T cells (12). Moreover, we observed that these antitumor T cells were already present in the blood of these patients at similar frequencies before vaccination.…”

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

“…It was shown by Germeau and colleagues that large numbers of antitumor T cells are already present within melanoma patients prior to vaccination with tumor antigens. 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].…”

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…However, clinical studies using high-affinity MART-1 TCR-engineered T cells showed severe toxicity, including the destruction of normal melanocytes in the skin, eye, and ear, and sometimes requiring local steroid administration to treat uveitis and hearing loss [203], compared with patient-derived TCR-engineered T cell therapy [206]. Similarly, serious toxicity was not observed with endogenous MAGE-A3-reactive T cells from cancer patients or patients vaccinated with a MAGE-A3 protein [188,207]. MAGE-A3 is highly expressed in cancer cells, but not in normal cells.…”