Short-Term Kinetics of Tumor Antigen Expression in Response to Vaccination

Abstract

The melanoma patient’s immune response to tumor has been extensively studied. Yet, the frequently observed coexistence of tumor-associated Ag (TAA)-specific T cells with their target cells in vivo remains unexplained. Loss of TAA expression might contribute to this paradox. We studied TAA expression in metastases by obtaining fine-needle aspirations from 52 tumor lesions in 30 patients with melanoma before and soon after immunotherapy. Limitations due to low amounts of starting material were overcome with a high fidelity antisense RNA amplification method. TAA expression was measured by quantitative real-time PCR of anti-sense RNA. Decrease in gp100/Pmel-17 TAA preceded tumor disappearance in several instances and could be best explained by immune selection because most patients had received gp100/Pmel-17-specific vaccination. Conversely, immune selection was absent in nonregressing lesions. These observations suggest that vaccination, when successful, triggers a broad inflammatory reaction that can lead to tumor destruction despite immune selection. Additionally, lack of clinical response might be attributed to lack of this initiating event rather than immune escape. This study provides an insight into the natural history of tumors and defines a strategy for the characterization of gene expression in tumors during therapy.

Unmasking cryptic epitopes after loss of immunodominant tumor antigen expression through epitope spreading

“…MAGE-12 is expressed in approximately 80% of melanoma metastases, however, and the shortterm kinetics of its expression in response to immune manipulation seems to be extremely stable. 30 The expression of the associated HLA-Cw*0702 allele might have played a role in the emergence of this unusual reactivity. Increases in the constitutive expression of HLA alleles are unusual in cancer, however, unless an altered cytokine microenvironment (i.e., increased IFN-␥ levels) could have been induced by immune cells accrued by the vaccine.…”

Melanoma‐associated chondroitin sulphate proteoglycan as a new target antigen for CD4+ T cells in melanoma patients

“…1 One obstacle might be immune escape by downregulation or complete loss of antigen expression as many antigens identified so far do not play an essential functional role for the tumor. [2][3][4] To overcome this it would be particularly important to choose a suitable target antigen for vaccination therapy, which should be broadly expressed and functionally relevant for the tumor. On our search for suitable target antigens for the active-specific immunotherapy of melanoma, we focused on the human melanoma-associated chondroitin sulfate proteoglycan (MCSP), also known as high molecular weight-melanoma-associated antigen, which has been shown to be expressed in the majority of human melanoma lesions and cultured cells with a limited expression in normal tissues.…”

Melanoma antigen expression in serial fine-needle aspiration samples in patients with metastatic malignant melanoma participating in immunotherapy clinical trials

“…Clinical trials using immunodominant peptides from melanoma associated antigens and recombinant adenoviruses coding human MAA for the treatment of patients with melanoma are ongoing at the NCI. [1][2][3][4][5][6][7][8][9] Melanoma antigens associated with HLA-A*0201, 11,12 which include MART-1/Melan A, 13,14 gp100/Pmel 17, 9 tyrosinase, 15 MAGE-3, 16 and N-acetylglucosaminyltransferase V, 17 are shared by most melanoma cells. The T-cell epitopes responsible for recognition of MAA have led to the development of vaccination pro- tocols based on the administration of short peptides representing such epitopes to patients with MMM.…”

“…18 Peptide vaccination protocols at the NCI are varied; however, several schedules consist of vaccination every 3 weeks for a total of 4 doses. 4,5 Recent data suggest that peptide-based immunization directed against gp100 and/or MART-1 is both powerful and specific, capable of inducing clinical responses. [1][2][3][4][5][6] Patients are selected for antigen specific immunotherapy according to antigen expression assessed by immunocytochemistry, which provides information about the intensity and homogeneity of antigen expression.…”

“…Fine-needle aspiration allows for the sampling of the same metastatic lesion at various timepoints thereby enabling the direct evaluation of the therapy over time on any given lesion while the lesion remains in vivo. 1,[3][4][5] Peptide vaccination against melanoma antigens can produce a powerful systemic cytotoxic T-lymphocyte response. 9 It is theorized that antigen expression may be diminished due to selective immunodestruction of tumor cells, or perhaps intentionally, to escape immunosurveillance.…”