Resident Physician University of Virginia Health Charlottesville, Virginia, United States
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Participants should be aware of the following financial/non-financial relationships:
Christine A. Tran, MD: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Introduction: Melanoma regression relies on melanoma-reactive T cells and their ability to infiltrate tumor. Cancer vaccines increase circulating T cells, but a question is if circulating vaccine-induced T lymphocytes (cVILs) home to tumor. It was hypothesized that cVILs infiltrate melanoma metastases and intratumoral IFNγ or topical TLR7 agonist enhance infiltration.
Methods: Mel51 (NCT00977145) and Mel53 (NCT01264731) patients received vaccines with 12 class I MHC-restricted melanoma peptides and class II MHC-restricted tetanus toxoid-derived helper peptide, and provided blood samples. Tumor was injected with IFNγ on day 22 in Mel51, and biopsied on days 1, 22 and 24 (Fig 1A). Imiquimod, a TLR7 agonist, was applied to dermal metastases for six weeks in Mel53. Tumors were biopsied on days 1, 22 and 43 (Fig 1B). DNA was extracted from peripheral blood mononuclear cells (PBMC) pre-vaccine and at peak T cell response and underwent T cell receptor (TCR) sequencing. DNA was extracted from sampled tumor biopsies and underwent TCR sequencing. These sequences were cross referenced with PBMC sequences for overlapping ones present in tumor post-vaccine but not pre-vaccine.
Results: All patients had expanded cVILs in PBMC post-vaccine and overlapping sequence upregulation in PBMC and tumor post-vaccine, patient 1 having the largest response (Fig 1C). Mel51 patients had TCR sequence upregulation in tumor post-vaccine and pre-IFNγ, except for patient 1 (mean=7.5, median=13, range=0-24). This increased after IFNγ for all tumors evaluable on day 24 (mean=44.7, median=49, range=11-74) (Fig 1D-E). Mel53 patients had TCR sequence upregulation in tumor post-vaccine (mean=33, median=33, range=2-64). Patients 2 and 3 had new clones in tumor post-vaccine, which increased with IFNγ, with clones on day 22 persisting on day 24 (Fig 1F-G). Patient 5 had new clones present in tumor on day 22, which increased with imiquimod, with clones on day 22 persisting on day 24 (Fig 1H).
Conclusions: Cancer vaccines induce new T cells, and intratumoral IFNγ or topical imiquimod enhances cVIL tumor infiltration. These studies show that cVILs can home to tumor and reinforce the use of vaccine trials in melanoma.
Learning Objectives:
Illustrate the ability of cancer vaccines to induce the generation of novel T cell clones that are reactive to tumor antigens.
Describe the potential role of intratumoral IFNγ or topical TLR7 agonist as an adjunct treatment in the treatment of melanoma.
Understand the clinical implications of vaccine trials in melanoma and their potential impact on the treatment of melanoma.
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