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Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in soft tissue sarcomas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Canis lupus familiaris

PROVIDER: GSE218914 | GEO | 2023/03/01

REPOSITORIES: GEO

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Collagen-Anchored Interleukin-2 and Interleukin-12 Safely Reprogram the Tumor Microenvironment in Canine Soft-Tissue Sarcomas.

Project description:PurposeCytokine therapies such as IL2 and IL12 suffer from impractically small therapeutic windows driven by their on-target, off-tumor activity, limiting their clinical potential despite potent antitumor effects. We previously engineered cytokines that bind and anchor to tumor collagen following intratumoral injection, and sought to test their safety and biomarker activity in spontaneous canine soft-tissue sarcomas (STS).Experimental designCollagen-binding cytokines were canine-ized to minimize immunogenicity and were used in a rapid dose-escalation study in healthy beagles to identify a maximum tolerated dose. Ten client-owned pet dogs with STS were then enrolled into trial, receiving cytokines at different intervals prior to surgical tumor excision. Tumor tissue was analyzed through IHC and NanoString RNA profiling for dynamic changes within treated tumors. Archived, untreated STS samples were analyzed in parallel as controls.ResultsIntratumorally administered collagen-binding IL2 and IL12 were well tolerated by STS-bearing dogs, with only Grade 1/2 adverse events observed (mild fever, thrombocytopenia, neutropenia). IHC revealed enhanced T-cell infiltrates, corroborated by an enhancement in gene expression associated with cytotoxic immune function. We found concordant increases in expression of counter-regulatory genes that we hypothesize would contribute to a transient antitumor effect, and confirmed in mouse models that combination therapy to inhibit this counter-regulation can improve responses to cytokine therapy.ConclusionsThese results support the safety and activity of intratumorally delivered, collagen-anchoring cytokines for inflammatory polarization of the canine STS tumor microenvironment. We are further evaluating the efficacy of this approach in additional canine cancers, including oral malignant melanoma.

| S-EPMC10239368 | biostudies-literature

Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in canine soft tissue sarcomas

Project description:Canine soft tissue sarcomas were analyzed for gene expression changes following intratumoral treatment with collagen-anchored IL-2 and IL-12 therapy. Tumors were surgically resected at different intervals following treatment to assess persistence of any therapy-driven gene expression changes.

2023-03-01 | GSE218912 | GEO

Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in mouse melanomas

Project description:Mouse B16F10 melanoma tumors were analyzed for gene expression changes following intratumoral treatment with collagen-anchored IL-2 and IL-12 therapy for comparative analysis to expression changes observed in canine soft tissue sarcomas. Tumors were collected at different intervals following treatment to assess persistence of any therapy-driven gene expression changes.

2023-03-01 | GSE218913 | GEO

Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in soft tissue sarcomas

Project description:Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in soft tissue sarcomas

| PRJNA906123 | ENA

Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in canine soft tissue sarcomas

Project description:Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in canine soft tissue sarcomas

| PRJNA906127 | ENA

Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in mouse melanomas

Project description:Collagen-anchored interleukin-2 and interleukin-12 safely reprogram the tumor microenvironment in mouse melanomas

| PRJNA906126 | ENA

Immune Cells in the Tumor Microenvironment of Soft Tissue Sarcomas.

Project description:Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent.

| S-EPMC10741982 | biostudies-literature

Trabectedin in soft tissue sarcomas.

Project description:Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression-free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas.

| S-EPMC4344612 | biostudies-literature

New therapeutics for soft tissue sarcomas: Overview of current immunotherapy and future directions of soft tissue sarcomas.

Project description:Soft tissue sarcoma is a rare and aggressive disease with a 40 to 50% metastasis rate. The limited efficacy of traditional approaches with surgery, radiation, and chemotherapy has prompted research in novel immunotherapy for soft tissue sarcoma. Immune checkpoint inhibitors such as anti-CTLA-4 and PD-1 therapies in STS have demonstrated histologic-specific responses. Some combinations of immunotherapy with chemotherapy, TKI, and radiation were effective. STS is considered a 'cold', non-inflamed tumor. Adoptive cell therapies are actively investigated in STS to enhance immune response. Genetically modified T-cell receptor therapy targeting cancer testis antigens such as NY-ESO-1 and MAGE-A4 demonstrated durable responses, especially in synovial sarcoma. Two early HER2-CAR T-cell trials have achieved stable disease in some patients. In the future, CAR-T cell therapies will find more specific targets in STS with a reliable response. Early recognition of T-cell induced cytokine release syndrome is crucial, which can be alleviated by immunosuppression such as steroids. Further understanding of the immune subtypes and biomarkers will promote the advancement of soft tissue sarcoma treatment.

| S-EPMC10052453 | biostudies-literature

Cellular immunotherapy for soft tissue sarcomas.

Project description:Soft tissue sarcomas are rare neoplasms, with approximately 9000 new cases in the USA every year. Unfortunately, during the past two decades, there has been little progress in the treatment of metastatic soft tissue sarcomas beyond the standard approaches of surgery, chemotherapy and radiation. Immunotherapy is a modality complementary to conventional therapy. It is appealing because functional antitumor activity could affect both local-regional and systemic disease, and act over a prolonged period of time. In this report, we review immunotherapeutic investigative strategies that are being developed, including several tumor vaccine, antigen vaccine and dendritic cell vaccine strategies.

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