Procaspase-3 activation and immunotherapy for treatment of cancer
A caspase, cancer vaccine technology for precursor caspase-3 activation and immunotherapy for the treatment of cancer that addresses lack of efficacy
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[0116] Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in an appropriate solvent with various other ingredients enumerated above, if necessary, followed by filtered sterilization, as required. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation may include vacuum drying and freeze-drying techniques which form a powder of the active ingredient plus any additional ingredients required in solution.
[0117] For topical administration, the compounds may be used in pure form, for example when they are liquids. Generally, however, it is desired to apply the active agent to the skin, eg, in a composition or formulation in combination with a dermatologically acceptable carrier, which may be a solid, liquid, gel, or the like.
[0118] Useful solid carriers include finely divided solids such as talc, clays, microcrystalline cellulose, silica, alumina, and the like. Useful li...
Embodiment 1
[0131] Example 1. Experimental procedure on the 4T1 efficacy model.
[0132] Reagents: The following antibodies were purchased from Bio x Cell: anti-mouse CTLA-4 monoclonal antibody (anti-mouse CTLA-4 monoclonal antibody, 9H10), anti-mouse PD-1 monoclonal antibody (anti-mouse PD-1 monoclonal antibody , RMP1-14), rat IgG2A isotype control (rat IgG2a isotype control, 2A3) and polyclonal Syrian hamster IgG (polyclonal Syrian hamster IgG).
[0133] Cell line: 4T1 murine breast cancer cell line was obtained from ATCC and grown in CO 2 They were cultured in complete RPMI1640 containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37° C. in an incubator.
[0134] 4T1 Orthotopic Tumor Model: All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Illinois at Urbana-Champaign. Female BALB / c mice aged 6-8 weeks were purchased from Charles River and allowed to acclimate for 7 days. Mice were lightly sedated with ...
Embodiment 2
[0136] Example 2. Tumor Research
[0137] Increased immune cell infiltration in PAC-1-treated GL261 tumors: In addition to the data showing that PAC-1 induces caspase-3-mediated cleavage of MLH1 in cancer cells, there are many other lines of evidence supporting the association of PAC-1 with immunotherapy strategies (including examining Synergistic combination of point inhibitors and neoantigen vaccines): 1) Transcriptional profiling of PAC-1-treated cancer cells showed upregulation of key genes including TNFα, innate immune system agonists IL-1 and IL-8, and were associated with anti-PD -1 Resistance-related markers are not upregulated by therapy (IPRES: eg CCL2, CCL7, CCL8, CCL13, etc.). 2) The work of another research group showed that PAC-1 can enhance extrinsic cell death in culture through a combination study with the immune cytokine TRAIL. 3) PAC-1 is effective in an in vivo setting with an intact immune system, including syngeneic mice (EL4, K7M2, GL261) ( Figure 7 )...
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