IL-12 and PD-1 peptide combination gene therapy for the treatment of melanoma
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ABSTRACT:
SUBMITTER: Heller L
PROVIDER: S-EPMC11339250 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Project description:Like many effective therapeutics, interleukin-12 (IL-12) therapy often causes side effects. Tumor targeted delivery may improve the efficacy and decrease the toxicity of systemic IL-12 treatments. In this study, a novel targeting approach was investigated. A secreted alkaline phosphatase (SEAP) reporter gene-based screening process was used to identify a mini-peptide which can be produced in vivo to target gene products to tumors. The coding region for the best peptide was inserted into an IL-12 gene to determine the antitumor efficacy. Affinity chromatography, mass spectrometry analysis, and binding studies were used to identify a receptor for this peptide. We discovered that the linear peptide VNTANST increased the tumor accumulation of the reporter gene products in five independent tumor models including one human xenogeneic model. The product from VNTANST-IL-12 fusion gene therapy increased accumulation of IL-12 in the tumor environment, and in three tumor models, VNTANST-IL-12 gene therapy inhibited distal tumor growth. In a spontaneous lung metastasis model, inhibition of metastatic tumor growth was improved compared to wild-type IL-12 gene therapy, and in a squamous cell carcinoma model, toxic liver lesions were reduced. The receptor for VNTANST was identified as vimentin. These results show the promise of using VNTANST to improve IL-12 treatments.
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Project description:Cancer immunotherapy is a new therapeutic strategy for cancer treatment that targets tumors by improving or restoring immune system function. Therapies targeting immune checkpoint molecules have exerted potent anti-tumor effects and prolonged the overall survival rate of patients. However, only a small number of patients benefit from the treatment. Oncolytic viruses exert anti-tumor effects by regulating the tumor microenvironment and affecting multiple steps of tumor immune circulation. In this study, we engineered two oncolytic viruses that express mouse anti-PD-1 antibody (VT1093M) or mouse IL-12 (VT1092M). We found that both oncolytic viruses showed significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Importantly, the intratumoral combined injection with VT1092M and VT1093M inhibited growth of the primary tumor, prevented growth of the contralateral untreated tumor, produced a vaccine-like response, activated antigen-specific T cell responses and prolonged the overall survival rate of mice. These results indicate that combination therapy with the engineered oncolytic virus may represent a potent immunotherapy strategy for cancer patients, especially those resistant to PD-1/PD-L1 blockade therapy.
| S-EPMC8607272 | biostudies-literature
Project description:PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.
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Project description:Hepatocellular carcinoma (HCC) and solid cancers with liver metastases are indications with high unmet medical need. Interleukin-12 (IL-12) is a proinflammatory cytokine with substantial anti-tumor properties, but its therapeutic potential has not been realized due to severe toxicity. Here, we show that orthotopic liver tumors in mice can be treated by targeting hepatocytes via systemic delivery of adeno-associated virus (AAV) vectors carrying the murine IL-12 gene. Controlled cytokine production was achieved in vivo by using the tetracycline-inducible K19 riboswitch. AAV-mediated expression of IL-12 led to STAT4 phosphorylation, interferon-γ (IFNγ) production, infiltration of T cells and, ultimately, tumor regression. By detailed analyses of efficacy and tolerability in healthy and tumor-bearing animals, we could define a safe and efficacious vector dose. As a potential clinical candidate, we characterized vectors carrying the human IL-12 (huIL-12) gene. In mice, bioactive human IL-12 was expressed in a vector dose-dependent manner and could be induced by tetracycline, suggesting tissue-specific AAV vectors with riboswitch-controlled expression of highly potent proinflammatory cytokines as an attractive approach for vector-based cancer immunotherapy.
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Project description:Electrochemotherapy (ECT) is a standard of care in veterinary and human oncology. The treatment induces a well-characterized local immune response which is not able to induce a systemic response. In this retrospective cohort study, we evaluated the addition of gene electrotransfer (GET) of canine IL-2 peritumorally and IL-12 intramuscularly to enhance the immune response. Thirty canine patients with inoperable oral malignant melanoma were included. Ten patients received ECT+GET as the treatment group, while twenty patients received ECT as the control group. Intravenous bleomycin for the ECT was used in both groups. All patients had compromised lymph nodes which were surgically removed. Plasma levels of interleukins, local response rate, overall survival, and progression-free survival were evaluated. The results show that IL-2 and IL-12 expression peaked around days 7-14 after transfection. Both groups showed similar local response rates and overall survival times. However, progression-free survival resulted significantly better in the ECT+GET group, which is a better indicator than overall survival, as it is not influenced by the criterion used for performing euthanasia. We can conclude that the combination of ECT+GET using IL-2 and IL-12 improves treatment outcomes by slowing down tumoral progression in stage III-IV inoperable canine oral malignant melanoma.
| S-EPMC10301420 | biostudies-literature
Project description:Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
| S-EPMC9793890 | biostudies-literature
Project description:Melanoma is the deadliest type of skin cancer with one of the fastest increasing incidence rates among solid tumors. The use of checkpoint inhibitors (e.g. αPD-1 antibody) has recently emerged as a viable alternative to conventional modes of therapy. However, increasing evidence points towards the need for a tumor priming step to improve intratumoral immune cell infiltration. IL-12 is an immune-activating cytokine with such potential and was explored in earlier clinical trials as a highly concentrated systemic infusion. This unfortunately led to severe adverse effects. From this perspective, the localization and gradual release of such a potent immunotherapeutic agent in the tumor microenvironment is desired. This manuscript reports the use of a heparin-based complex coacervate to deliver IL-12, in which heparin-binding motifs on IL-12 allow for its effective encapsulation. IL-12-encapsulated complex coacervates significantly improved the bioactivity of IL-12 and provided protection from proteolytic cleavage in-vitro. Indeed, a single injection of IL-12 coacervate significantly inhibits the in-vivo growth of treated and untreated, contralateral tumor growth in a syngeneic B16F10 mouse melanoma model. Furthermore, tumors in mice receiving IL-12 complex coacervate treatment displayed increased infiltration by natural killer (NK) cells and CD8α+ T cells, and a decreased presence of CD4+Foxp3+ regulatory T cells. This study provides proof-of-concept data supporting the use of complex coacervates for sustained delivery of immunostimulatory proteins as an effective therapeutic strategy against disseminated tumors.
| S-EPMC7045464 | biostudies-literature
Project description:Intratumoral electroporation-mediated IL-12 gene therapy (IT-pIL12/EP) has been shown to be safe and effective in clinical trials, demonstrating systemic antitumor effects with local delivery of this potent cytokine. We recently optimized our IL-12 gene delivery platform to increase transgene expression and efficacy in preclinical models. Here we analyze the immunological changes induced with the new IT-pIL12/EP platform in both electroporated and distant, non-electroporated lesions. IT-pIL12/EP-treated tumors demonstrated rapid induction of IL-12-regulated pathways, as well as other cytokines and chemokines pathways, and upregulation of antigen presentation machinery. The distant tumors showed an increase in infiltrating lymphocytes and gene expression changes indicative of a de novo immune response in these untreated lesions. Flow cytometric analyses revealed a KLRG1hi CD8+ effector T-cell population uniquely present in mice treated with IT-pIL12/EP. Despite being highly activated, this population expressed diminished levels of PD-1 when re-exposed to antigen in the PD-L1-rich tumor. Other T-cell exhaustion markers appeared to be downregulated in concert, suggesting an orchestrated "armoring" of these effector T cells against T-cell checkpoints when primed in the presence of IL-12 in situ. These cells may represent an important mechanism by which local IL-12 gene therapy can induce a systemic antitumor immune response without the associated toxicity of systemic IL-12 exposure.
| S-EPMC6514882 | biostudies-literature
Project description:BACKGROUND:Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases. Here, we present a case of MUM treated with combination immune checkpoint therapy (ipilimumab and nivolumab) following the progression with single-agent nivolumab and demonstrating a durable response without recurrence more than 22 months from the last treatment. CASE PRESENTATION:A 72-year-old Caucasian man presented with ciliary body melanoma of the left eye and underwent curative-intent enucleation but six months later developed diffuse hepatic metastases. He initially was treated with nivolumab 3 mg/kg every two weeks for four cycles but restaging scan showed a significant progression of the disease with increasing LDH. With the FDA approval for the combination of nivolumab 1mg/kg with Ipilimumab 3 mg/kg every three weeks for metastatic melanoma, this combination was given for four cycles with continuous rise in LDH to 993 unit/L (110-220 unit/L) until finishing cycle four of the treatment. Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity with ALT 1565 unit/L (0-55 unit/L). A presumptive diagnosis of autoimmune hepatitis was made, nivolumab was stopped and oral prednisone 1mg/kg was started with quick resolution of elevated transaminases. Restaging abdominal MRI one month after the first and last dose of maintenance nivolumab showed PR and continuous shrinkage of the metastatic lesions with no hypermetabolic activity even on PET/CT. He is 22 months' post-treatment and continues to do well without any evidence of active disease. CONCLUSION:Although, limited response has been shown to single agent immune checkpoint inhibitors and chemotherapy, our patient showed durable response with anti-CTLA-4 and anti-PD-1 combination therapy in MUM.
| S-EPMC5809910 | biostudies-literature
Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.
2024-01-26 | PXD044740 | Pride