The Trick With Senolytics
How understanding and manipulating senescence dynamics could optimize cancer therapies and improve patient outcomes.
| 4 min read | Interview
A November 2024 publication in Nature Communications confirmed the fundamental role of senescent cells in cancer progression, and uncovered a mechanism that enables cancer cells to evade immune responses. The research, led by the Faculty of Medicine and Health Technology, Tampere University, Finland, evaluated 120 prostate cancer patients and found that the cells that contribute to immune suppression possess a senescent profile.
Florida-based life extension company Immorta Bio is developing a senolytic platform to remove senescent cells as an immunotherapy. So far, the company has demonstrated potent reduction of cancer growth and regression in animal models of lung cancer, breast cancer, skin cancer, glioma, and pancreatic cancer. An IND application was submitted to the US FDA earlier in 2024, so we spoke to Chief Scientific Officer Thomas Ichim to find out how it works, and what happens next.
How does a senolytic approach specifically target cancer cells without affecting healthy cells?
SenoVax is our first-in-class immunotherapeutic candidate in the pre-clinical stage designed to selectively eliminate senescent cells that surround cancer cells. Senescent cells accumulate in and around tumors, contributing to cancer progression and resistance to therapy. They exhibit altered gene expression profiles, including upregulation of senescence-associated secretory phenotype (SASP) factors and specific surface markers that are not present on healthy cells.
Our drug candidate exploits these differences by stimulating both antibody and T-cell-mediated immune responses to selectively eliminate senescent cells. The precision induces apoptosis in senescent cancer cells while sparing normal, healthy cells, thereby minimizing collateral damage and adverse side effects.
What are the mechanisms used to clear senescent cells in advanced lung cancer?
SenoVax consists of patient-specific lysed fibroblast cells loaded onto autologous dendritic cells. Administration of dendritic cells containing senescent cell-associated antigens induces a potent T helper 1 (Th1) cellular immune response against senescent cells. This type of immune response clears senescent cells by direct cytotoxic T-cell-mediated killing, as well as antibody-mediated killing and/or inactivation through antibody-dependent cytotoxicity and complement activation. Recent scientific findings, including those published in Nature Communications, have highlighted the effectiveness of senolytic therapies in eliminating senescent cells and enhancing treatment outcomes.
How does SenoVax compare to existing immunotherapies?
Conventional therapies target cancer cells that mutate and protect themselves by avoiding drugs. Senescent cells do not mutate, so targeting them could help circumvent the development of resistance. While immunotherapies activate the immune system to attack cancer cells, which can sometimes lead to immune-related adverse events, SenoVax targets the senescent cells that protect cancer cells without broadly stimulating the immune system. This specificity may reduce the risk of side effects commonly associated with immunotherapies, such as cytokine release syndrome or autoimmune reactions. In terms of efficacy, by addressing a fundamental mechanism of tumor persistence, we are working to develop an immunotherapy with the potential to improve patient outcomes.
What are the initial results from preclinical studies?
Preclinical studies demonstrated that the drug candidate effectively reduces the population of senescent cells in tumor models of advanced lung cancer. Treatment led to significant decreases in tumor size and a reduction in metastatic spread in animal models. Additionally, there was an improvement in overall survival rates without notable toxicity or adverse effects on healthy tissues. These findings are supported by recent scientific publications, indicating the effectiveness of senolytic therapies in cancer treatment. Our preclinical data provided a strong rationale for progressing to clinical trials, suggesting that SenoVax could offer substantial therapeutic benefits to patients with advanced lung cancer, melanoma, pancreatic, breast, and brain cancer.
Do you anticipate any scaling-up challenges further along the process?
SenoVax is a personalized cancer immunotherapy, meaning that its dose needs to be generated in a patient-specific manner. This requires central GMP laboratories in multiple geographic regions. Scaling up involves expanding our senolytic technology to treat other types of cancer and forming strategic partnerships for out-licensing. One challenge is adapting SenoVax to target senescent cells in different tumor microenvironments, which may require additional research and development. To address this, we are investing in preclinical studies across various cancer models to validate its efficacy beyond lung cancer.
What's next for this project?
The field of senolytic therapies is rapidly evolving, with growing evidence supporting their role in cancer treatment. Future research will likely focus on expanding to other cancer types, and building on success in lung cancer to treat other malignancies where senescent cells contribute to disease progression.
Combination therapies and integrating senolytics with immunotherapies, chemotherapies, or targeted therapies to enhance overall efficacy, as well as the development of patient-specific treatments based on the senescence profile of individual tumors, are other potential areas of research. By identifying novel biomarkers for better patient selection and monitoring, and through collaborating with industrial stakeholders to accelerate development and commercialization efforts, the goal overall is to contribute significantly to the elimination of cancer.
Senescence in Cancer Cells
Senescence is a state in which cells stop dividing but remain metabolically active. It is triggered by various stressors, such as DNA damage, oncogene activation, or aging-related signals. While senescence helps prevent damaged or abnormal cells from proliferating, it can contribute to aging and chronic inflammation. Senescent cells release signaling molecules that influence their environment that can promote tissue repair or, conversely, drive disease processes. In cancer, senescence plays a dual role as both a tumor-suppressive mechanism and a potential promoter of malignancy.
Senescence acts as a critical barrier against tumorigenesis by halting the proliferation of cells with oncogenic mutations or severe genomic instability. The senescence-associated secretory phenotype releases pro-inflammatory cytokines, growth factors, and proteases, which can recruit immune cells to clear senescent cells from the tumor microenvironment and help prevent cancer progression.
However, cancer cells can exploit senescence-related pathways. The SASP can create a pro-tumorigenic environment, fostering angiogenesis, invasion, and immune evasion. Senescent cells that escape immune clearance may accumulate and contribute to chronic inflammation, aiding tumor progression. Chemotherapy or radiotherapy can induce senescence in cancer cells, but the persistence can lead to resistance or recurrence.
