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Identification of TIM3 2'-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy
Sandra Hervas-Stubbs1,2, Mario M Soldevilla2,3, Helena Villanueva2,3
1Program Immunology and Immunotherapy, Centro de Investigaciones Medicas Aplicadas (CIMA), Pamplona, Spain.
Abstract:
TIM3 belongs to a family of receptors that are involved in T-cell exhaustion and Treg functions. The development of new therapeutic agents to block this type of receptors is opening a new avenue in cancer immunotherapy. There are currently several clinical trials ongoing to combine different immune-checkpoint blockades to improve the outcome of cancer patients. Among these combinations we should underline PD1:PDL1 axis and TIM3 blockade, which have shown very promising results in preclinical settings. Most of these types of therapeutic agents are protein cell-derived products, which, although broadly used in clinical settings, are still subject to important limitations. In this work we identify by HT-SELEX TIM3 non-antigenic oligonucleotide aptamers (TIM3Apt) that bind with high affinity and specificity to the extracellular motives of TIM3 on the cell surface. The TIM3Apt1 in its monomeric form displays a potent antagonist capacity on TIM3-expressing lymphocytes, determining the increase of IFN-γ secretion. In colon carcinoma tumor-bearing mice, the combinatorial treatment of TIM3Apt1 and PDL1-antibody blockade is synergistic with a remarkable antitumor effect. Immunotherapeutic aptamers could represent an attractive alternative to monoclonal antibodies, as they exhibit important advantages; namely, lower antigenicity, being chemically synthesized agents with a lower price of manufacture, providing higher malleability, and antidote availability.
Insights
New aptamers targeting TIM3 receptors offer a promising cancer immunotherapy approach. Combining TIM3 aptamers with PDL1 blockade shows significant antitumor effects in preclinical models.
Area of Science:
- Immunology
- Biotechnology
- Oncology
Background:
- T-cell immunoglobulin and mucin-domain containing-3 (TIM3) receptors are crucial in T-cell exhaustion and regulatory T-cell (Treg) functions.
- Blocking immune checkpoints like TIM3 and PD1:PDL1 is a key strategy in cancer immunotherapy.
- Current protein-based therapeutics face limitations, necessitating novel approaches.
Purpose of the Study:
- To identify novel, non-antigenic oligonucleotide aptamers targeting TIM3.
- To evaluate the therapeutic potential of these aptamers, individually and in combination with PDL1 blockade, for cancer treatment.
Main Methods:
- High-throughput SELEX (HT-SELEX) was used to identify TIM3 aptamers (TIM3Apt).
- TIM3Apt1's antagonist capacity was assessed by measuring IFN-γ secretion in TIM3-expressing lymphocytes.
- Synergistic antitumor effects were evaluated in colon carcinoma tumor-bearing mice using a combination of TIM3Apt1 and PDL1 antibody blockade.
Main Results:
- High-affinity, specific TIM3 aptamers (TIM3Apt) were identified, binding to TIM3 on the cell surface.
- TIM3Apt1 demonstrated potent antagonist activity, increasing IFN-γ secretion.
- The combination of TIM3Apt1 and PDL1 blockade exhibited synergistic antitumor effects in a preclinical colon carcinoma model.
Conclusions:
- TIM3 aptamers are effective antagonists of TIM3 signaling and can enhance anti-tumor immunity.
- Aptamers represent a viable alternative to monoclonal antibodies in cancer immunotherapy due to advantages like lower antigenicity and cost.
- Combination therapy with TIM3 aptamers and PDL1 blockade shows significant therapeutic promise for cancer treatment.
