Targeting 4-1BB costimulation to disseminated tumor lesions with bi-specific oligonucleotide aptamers

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Limited costimulation at tumor sites hinders T cell-mediated tumor elimination.
• Developing strategies to enhance the tumor microenvironment's costimulatory signals is crucial for effective cancer immunotherapy.

Purpose of the Study:

• To investigate the efficacy of bi-specific oligonucleotide aptamer conjugates for delivering costimulatory ligands directly to tumor cells.
• To evaluate the potential of aptamer-mediated costimulation in enhancing antitumor immunity and controlling tumor growth.

Main Methods:

• Systemic delivery of a 4-1BB agonistic aptamer ligand conjugated to a prostate-specific membrane antigen (PSMA)-binding aptamer.
• Testing in poorly immunogenic subcutaneous tumor and lung metastasis models.
• Assessing tumor growth inhibition, synergy with vaccination, and therapeutic index compared to antibody-based costimulation.

Main Results:

• Aptamer conjugates significantly inhibited tumor growth in preclinical models.
• Targeted costimulation demonstrated superior efficacy and synergy with vaccination compared to traditional methods.
• Tumor inhibition was dependent on PSMA-targeting and 4-1BB costimulation, confirming the mechanism of action.

Conclusions:

• Aptamer-targeted costimulation is a viable and clinically feasible strategy to enhance antitumor immunity.
• This approach can effectively augment the costimulatory environment in disseminated tumors.
• Potentiating natural antitumor immunity via targeted costimulation offers a promising avenue for cancer treatment.