Intratumoral IFN-γ or topical TLR7 agonist promotes infiltration of melanoma metastases by T lymphocytes expanded in the blood after cancer vaccine

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BACKGROUND: Immune-mediated melanoma regression relies on melanoma-reactive T cells infiltrating tumor. Cancer vaccines increase circulating melanoma-reactive T cells, but little is known about vaccine-induced circulating lymphocytes (viCLs) homing to tumor or whether interventions are needed to enhance infiltration. We hypothesized that viCLs infiltrate melanoma metastases, and intratumoral interferon (IFN)-γ or Toll-like receptor 7 (TLR7) agonism enhances infiltration.

METHODS: Patients on two clinical trials (Mel51 (NCT00977145), Mel53 (NCT01264731)) received vaccines containing 12 class I major histocompatibility complex-restricted melanoma peptides (12MP). In Mel51, tumor was injected with IFN-γ on day 22, and biopsied on days 1, 22, and 24. In Mel53, dermal metastases were treated with topical imiquimod, a TLR7 agonist, for 12 weeks, and biopsied on days 1, 22, and 43. For patients with circulating T-cell responses to 12MP by IFN-γ ELISpot assays, DNA was extracted from peripheral blood mononuclear cells (PBMCs) pre-vaccination and at peak T-cell response, and from tumor biopsies, which underwent T-cell receptor sequencing. This enabled identification of clonotypes induced in PBMCs post-vaccination (viCLs) and present in tumor post-vaccination, but not pre-vaccination.

RESULTS: Six patients with T-cell responses post-vaccination (Mel51 n = 4, Mel53 n = 2) were evaluated for viCLs and vaccine-induced tumor infiltrating lymphocytes (viTILs). All six patients had viCLs, five of whom were evaluable for viTILs in tumor post-vaccination alone. Mel51 patients had viTILs identified in day 22 tumors, post-vaccination and before IFN-γ (median = 2, range = 0-24). This increased in day 24 tumors after IFN-γ (median = 30, range = 4-74). Mel53 patients had viTILs identified in day 22 tumors, post-vaccination plus imiquimod (median = 33, range = 2-64). Three of five evaluable patients across both trials had viTILs with vaccination alone. All five had enhancement of viTILs with tumor-directed therapy. viTILs represented 0.0-2.9% of total T cells after vaccination alone, which increased to 0.6-8.7% after tumor-directed therapy.

CONCLUSION: Cancer vaccines induce expansion of new viCLs, which infiltrate melanoma metastases in some patients. Our findings identify opportunities to combine vaccines with tumor-directed therapies to enhance T-cell infiltration and T cell-mediated tumor control. These combinations hold promise in improving the therapeutic efficacy of antigen-specific therapies for solid malignancies.

Medienart:	E-Artikel

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	Zur Gesamtaufnahme - volume:11
Enthalten in:	Journal for immunotherapy of cancer - 11(2023), 2 vom: 06. Feb.

Sprache:	Englisch

Beteiligte Personen:	Tran, Christine A [VerfasserIn] Lynch, Kevin T [VerfasserIn] Meneveau, Max O [VerfasserIn] Katyal, Priya [VerfasserIn] Olson, Walter C [VerfasserIn] Slingluff, Craig L [VerfasserIn]

Links:	Volltext

Themen:	82115-62-6 Adjuvants, Immunologic CD8-Positive T-Lymphocytes Cancer Vaccines Imiquimod Interferon-gamma Journal Article Lymphocytes, Tumor-Infiltrating Melanoma P1QW714R7M Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't TLR7 protein, human Toll-Like Receptor 7 Tumor Microenvironment Vaccination

Anmerkungen:	Date Completed 08.02.2023 Date Revised 17.08.2023 published: Print ClinicalTrials.gov: NCT00977145, NCT01264731 Citation Status MEDLINE

doi:	10.1136/jitc-2022-005952

funding:
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PPN (Katalog-ID):	NLM352564806