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

Abstract

BackgroundImmune-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.MethodsPatients 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.ResultsSix 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.ConclusionCancer 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.

Immunotherapeutic Agents for Intratumoral Immunotherapy

“…In a recent clinical trial, patients with stage IIIB, IIIC or IV melanoma received an intratumoral IFNγ injection after they received a vaccine containing 12 class I major histocompatibility complex-restricted melanoma peptides that increased vaccine-induced tumor-infiltrating lymphocytes. This cancer vaccine and tumor-directed IFNγ treatment enhanced T-cell infiltration and T-cell-mediated tumor control [27].…”

Barriers to immune cell infiltration in tumors

“… 98 Direct injection of IFNγ into tumors of patients with melanoma, concurrent with a melanoma vaccine, increased CXCL10 expression in the tumor, but did not result in improved total T cell infiltration 97 ; however, there was selective increase in vaccine-specific T cells after IFNγ injection. 99 Even those encouraging findings are disappointing in that a median of only 2% of the total tumor-infiltrating lymphocytes were vaccine-induced. 99 Thus, low clinical response rates of immunogenic melanoma vaccines 100 are likely due to insufficient T cell homing signals within established human melanoma metastases, but intratumoral therapies with immune activating agents can overcome some of the tumor-associated barriers to infiltration.…”

“… 99 Even those encouraging findings are disappointing in that a median of only 2% of the total tumor-infiltrating lymphocytes were vaccine-induced. 99 Thus, low clinical response rates of immunogenic melanoma vaccines 100 are likely due to insufficient T cell homing signals within established human melanoma metastases, but intratumoral therapies with immune activating agents can overcome some of the tumor-associated barriers to infiltration. Similar opportunities may be worth exploring to enhance therapeutic effectiveness of chimeric antigen receptor (CAR)-T cells for solid tumors.…”

Unveiling the landscape of cytokine research in glioma immunotherapy: a scientometrics analysis

“…Given their profound impact on the immune response, numerous cytokines have been identified as promising therapeutic agents in oncology. In this context, several cytokines, such as recombinant IL-2 ( Sahin et al, 2020 ), IFNs ( Tran et al, 2023 ), and TNFs ( Gong et al, 2018 ; Zhu et al, 2018 ), have garnered clinical approval for use in immunotherapy. Their pivotal role in facilitating intercellular communication within the immune system underscores their potential in developing treatments for glioma.…”