UCLA Researchers in the Department of Microbiology, Immunology, & Molecular Genetics have utilized their previously developed computational method (IRIS), to process and capture small cell carcinoma-specific RNA splicing events in small cell cancer. These events and associated epitopes were then used as the basis for generating new T cell receptors (TCRs) that can be utilized for targeting and form the basis of novel pan-small cell cancer therapies.
BACKGROUND:
Small cell carcinoma is a highly aggressive form of tumor commonly arising from epithelial cancers with no effective treatment. Different small-cell cancers, such as small-cell prostate cancer (SCPC) and small-cell lung cancer (SCLC) are known to share convergent phenotypes. In the United States, there are about 34,000 new cases of SCLC diagnosed each year, and it is estimated that SCLC is responsible for about 25% of all lung cancer deaths. The current treatment approach for small cell carcinoma involves a combination of chemotherapy and radiation therapy, which can help to control cancer and prolong survival. However, the development of new therapies is still needed as the prognosis for small cell carcinoma is poor with a five-year survival rate of less than 10%. Despite the differing tissue of origin for these various small cell cancers, research into their genetic and molecular characteristics shows shared converging phenotypic features which can be exploited for developing both more specific and possibly pan-small cell cancer therapies to target multiple small cell cancers simultaneously.
INNOVATION:
UCLA Researchers in the laboratory of Dr. Owen Witte and from the Laboratory of Dr. Yi Xing have utilized their previously developed computational method, Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), to process and capture small cell carcinoma-specific RNA splicing events. Efforts utilizing SCPC as a starting point have identified 76 unique epitopes on HLA-A*02:01, including multiple events shared between SCPC and SCLC. Candidate epitopes were used to stimulate peripheral mononuclear cells (PBMCs) from healthy donors. Reactive T cells were then isolated and T cell receptors (TCRs) from recovered cells were retrieved by sequencing. Paired TCR alpha and beta chain were engineered and introduced into normal human PBMCs and tested for functionality. Through this approach, they have defined 12 highly efficient TCRs targeting 7 distinct small-cell cancer-enhanced splicing epitopes. These TCR/epitope pairings can be used as the foundation for developing new pan-small cell cancer therapies or in conjunction with existing targeting technologies.
POTENTIAL APPLICATIONS:
- Targeting of small cell lung cancer and small cell prostate cancer
- Pan-small cell cancer targeting approaches
- Selection of pan-small cell cancer-associated epitopes and TCRs
ADVANTAGES:
- Approach yields targets/TCRs that are pan-small cell cancer
- Multiple highly-specific TCR/epitope combinations selected
DEVELOPMENT-TO-DATE:
Method and treatment approaches have been tested and validated in vitro.
Related Papers (from the inventors only): Pan, Y., Phillips, J. W., Zhang, B. D., Noguchi, M., Kutschera, E., McLaughlin, J., Nesterenko, P. A., Mao, Z., Bangayan, N. J., Wang, R., Tran, W., Yang, H. T., Wang, Y., Xu, Y., Obusan, M. B., Cheng, D., Lee, A. H., Kadash-Edmondson, K. E., Champhekar, A., Puig-Saus, C., Ribas, A., Prins, R., Seet, C., Crooks, G., Witte, O., Xing, Y. (2023b). IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing. Proceedings of the National Academy of Sciences of the United States of America, 120(21). https://doi.org/10.1073/pnas.2221116120