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IL-2 cytokine therapy is currently used to treat melanoma. Intra-tumoral injection of cytokines is also being studied as a cancer immunotherapy approach. It is also proposed that after initial tumor tissue damage, negative feedback loops such as Treg proliferation will effectively restore immune to cytotoxic T cells. 9 It is also however suggested that radiotherapy may not address existing immune tolerance against tumor antigens. 8 It has also been reported that irradiation efficacy partly relies on the immune system and may generate antitumor immunity through immunogenic cell death, antigen release, MHC-I upregulation, and T-cell responses. 7 Like intra-tumoral drugs, local irradiation may induce systemic immune changes such as an increase in the levels of systemic cytokines and chemokines. It has also been reported that local tissue damage and inflammation induced by radiotherapy can generate tumor antigens and release danger-associated molecular patterns. In the biopsies carried out at injected sites, they found a significant decrease in CD25+/FoxP3+ T cells and antigen-presenting cells, and increased CD123+ pDCs upon intratumoral immunization. 6 reported an objective response rate in 5/14 mycosis fungoides patients when the same combination therapy in noninjected (abscopal) target lesions. An additional eight patients showed durable stable disease. reported an objective response rate of in 4/15 patients in noninjected target lesions. In other studies, intratumoral TLR agonists have been tested in combination with mild (2×2 Gy) local irradiation in patients with B- and T-cell lymphomas. In this study, T-cell receptor sequencing and flow cytometry demonstrated a decrease in clonal malignant T cells in 90% of the patients and a complete eradication in 30%.
#BRAFI TCEL FULL#
4 Partial benefit was reported in 75% of patients and full clinical benefit seen in 30% of the patients.
#BRAFI TCEL TRIAL#
Another topical TLR-7/8 agonist, Resiquimod, has been studied in a phase I trial of 12 patients with stage IA-IIA cutaneous T-cell lymphoma (CTCL) by Rook et al. 3 reported that in a clinical trial combining intralesional BCG with topical imiquimod in 9 melanoma patients, 5/9 patients experienced complete clinical benefit.
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A total of 182 tumor lesions were treated and anti-tumor responses reported in 92/182 lesions, with complete regression of 74 lesions. 2 In a reported phase I/II trial topical imiquimod in combination with intra-lesional interleukin (IL)-2, 13 patients with cutaneous melanoma metastases were tested. Imiquimod, which is a TLR-7/8 agonist, has demonstrated clinical antitumor activity and is approved for the treatment of superficial basal cell carcinomas, actinic keratosis, and genital warts. 1 Topical toll-like-receptor (TLR) agonists have been studied for their use in the treatment of cancer.
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Furthermore, direct injection into the tumor could not only reduce systemic exposure, off-target toxicities, and the amounts of drug used but also induce stronger antitumor activity in the injected tumor lesion and maybe in distant noninjected tumor lesions as well.
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Intra-tumoral injection generally defined as direct injection of immunostimulatory agents into the tumor itself, has the potential to result in superior priming of an antitumor response. Direct intra-tumoral injection of oncolytic viruses has recently been approved for the treatment of metastatic melanoma. Such agents include Bacillus Calmette-Guerin (BCG), oncolytic viruses, IL-2, small molecule STING agonist, toll receptor agonists and local irradiation of tumors. BACKGROUND OF THE INVENTIONĪ number of studies evaluating direct tumor injection as a means to generate anti-tumor immune responses at local and distal tumor sites have been evaluated in the clinic. Embodiments of the present disclosure relate generally to novel immunotherapeutic interventions, in particular, the use of cationic lipid-based vaccines, compositions and methods of use thereof, for direct tumor injection.
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