In the rapidly advancing world of medicine, recent breakthroughs in cell and gene therapy are revolutionizing the treatment of cancer and genetic diseases. These therapies, encompassing viral and nonviral vectors as well as mRNA, are transforming how we approach these complex conditions. However, one of the significant challenges facing these therapies is the need for reliable clinical trial endpoints that can accurately detect bioactivity and efficacy. Biomarkers—biological indicators related to molecular markers for disease—are emerging as a critical tool in this regard.

The latest special issue of *Molecular Therapy* titled “Targets and Biomarkers” delves into this very topic, highlighting the development of biomarkers and the clinical progression of innovative therapies, with a particular focus on cancer therapeutics.

 

Biomarkers in Genetic Disease Therapy

Monogenic inherited disorders, characterized by their single-gene defects, appear to be prime candidates for monitoring through biomarkers linked to the underlying genetic anomaly. Lysosomal storage disorders, caused by a deficiency in a single lysosomal enzyme, have been traditionally treated with enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation. Although these treatments represent the standard of care, they come with limitations, spurring the development of gene therapies now being tested in clinical trials. The accumulation of substrates within lysosomes serves as a biomarker and endpoint in these trials. However, as summarized by Rossi et al., despite the promise of imaging, laboratory, and novel biomarkers, no ideal markers have yet been identified for lysosomal storage diseases.

 

Advancements and Challenges in T Cell-Redirecting Therapies

T cell-redirecting therapies (TCRTs), including chimeric antigen receptor T (CAR-T) cells and T cell receptor T cells, have shown great promise in treating hematological malignancies. Yet, not all patients experience complete responses, and the absence of unique targets along with emerging toxicities have limited the effectiveness of TCRTs in some blood cancers and solid tumors. Anderson and Chapman provide a comprehensive review of specific surface immunotherapy targets across various hematologic malignancies, offering insights into strategies for identifying novel antigens for TCRT therapies, particularly in solid tumors. They acknowledge the lack of unique target proteins but highlight significant innovations in targeted TCRT therapies. Di Meo and colleagues further this discussion by exploring advancements in mass spectrometry-based platforms that enable the examination of the cancer cell surface proteome. This technology could potentially address the challenges faced by TCRT therapies by identifying specific cancer antigens with minimal off-target effects.

 

The Emerging Role of Noncanonical Microproteins in Immunomodulation

In a novel exploration, Nichols et al. shine a light on the world of noncanonical microproteins—proteins with fewer than 100 amino acids translated from small open reading frames. These microproteins, part of the so-called “dark proteome,” play roles in regulating immunity and cellular processes, areas only now beginning to be understood. Nichols and colleagues discuss the biology, identification, characterization, and immunomodulatory capabilities of microproteins, along with their potential applications as biomarkers, therapeutic targets, and agents.

 

RNA-Based Therapies: A New Frontier in Cancer Treatment

RNA-based therapies have rapidly emerged as versatile tools capable of restoring normal gene expression, modulating immune functions, and correcting various disease mechanisms. In a thorough review, Taibi et al. focus on the role of mRNA in cancer treatment, covering crucial aspects such as the production, design, and delivery of therapeutic mRNAs, as well as cancer vaccines. The potential of mRNA to enhance CAR-T cell therapies is also explored. Additionally, Muskan and colleagues discuss the use of extracellular vesicles (EVs) as delivery vehicles for different RNA types, including microRNA, mRNA, and circular RNA. They detail the therapeutic potential of RNA-enriched EVs across multiple diseases, including cancer. Lee et al. add to this conversation with a discussion on tissue-derived EVs as novel biomarkers and mediators in both normal physiology and disease.

 

Conclusion

The field of gene and cell therapy is advancing at an unprecedented pace. The development of new biomarkers holds the promise of advancing these therapies by providing reliable clinical trial endpoints that reflect the state of disease in individual patients. Improved targeting of these therapeutics to minimize toxicities and enhance effectiveness is likely to improve outcomes in clinical trials and pave the way for the approval of new therapies. As we continue to explore these innovative approaches, the future of cancer and genetic disease treatment looks increasingly promising.

Source:
https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(24)00532-X
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