UCLA researchers in the Departments of Medicine and Microbiology, Immunology and Molecular Genetics have developed a novel combination therapy for enhanced efficacy of Adoptive T Cell Therapies (ACT): that could enable the adoption of ACT as an effective means to combat multiple cancer subtypes.
BACKGROUND:
The clinical relevancy of cancer immunotherapy has grown exponentially in the past decade, showing little surprise that its market is expected to reach nearly $153 billion by 2024. The most promising clinical approach of immunotherapy has proven to be Adoptive T Cell Therapy (ACT), showing efficacy to treat cancers that conventional treatment strategies show poor effect for (e.g., small molecule chemotherapeutics, or surgical intervention). ACT utilizes the effective recognition of cancer cells through specific antigen presentation: lowering the significant incidence of off target toxicities common to other treatment strategies. In ACT, a patients’ T cells are removed, cultured ex vivo for population expansion, and then infused back into the patient. This pathway increases the number of T cells that can target cancer cells effectively. Unfortunately, there is mounting clinical evidence to suggest that many cancer subtypes can resist infiltration by these reinfused T cells, by utilizing the tumor microenvironment to weaken T cell activation. Research suggests that natural signaling pathways that activate lymphocytes, like cytokine signaling (e.g., interferons (IFNs)) may allow an effective means to promote T cell activation in the otherwise deleterious tumor microenvironment. However, injection of IFN is subject to rapid clearance due to systemic dilution, that leads to limited efficacy. Therefore, a great unmet need exists for novel approaches that with allow increased clinical efficacy of ACT.
INNOVATION:
Dr. Timmerman and colleagues have developed a novel methodology for enhancing the efficacy of ACT for cancer treatment. IFNs are infused to tumor-targeting antibodies as a payload, that can be directly delivered to the tumor site. Direct delivery of the IFN payload allows the T cells delivered by ACT, to overcome the tumor microenvironment and its effects in deactivating effector T cells. Murine model studies have shown that ACT therapy when combined with this payload method, results in double the tumor killing potential. Further studies elucidated that the IFN treatment led to significant increases in peripheral cytokine concentrations, that may further allow effector T cells the ability to overcome the tumor microenvironment. The presented methodology allows a unique and effective method for the direct delivery of cytokines that could allow increased clinical efficacy of ACT therapy: opening novel treatment strategies to various cancers that may lower incidences of off target toxicities observed in traditional treatment pathways.
POTENTIAL APPLICATIONS:
• Enhancement of adoptive cell therapy (ACT)
• Enhancement of CAR T cell therapy
ADVANTAGES:
• Combination treatment leads to improved tumor killing compared to T cell treatment alone
• Improved efficacy compared to combination therapy with antibody alone (rituximab)
• Cytokine levels are increased, causing sensitization of tumor cells
• IFN-antibody can target tumor sites in all locations of the body
DEVELOPMENT-TO-DATE:
IFN-antibody fusion proteins have been prepared and in vitro experiments using a variety of cell lines have demonstrated their efficacy when used in combination with adoptive cell therapy. Efficacy is improved compared to combination therapy with the FDA-approved rituximab.
RELATED PAPERS:
Xuan, C., Steward, K. K., Timmerman, J. M., & Morrison, S. L.(2010). Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma. Blood, 115(14),2864-2871.
Trinh KR, Vasuthasawat A, Steward KK, Yamada RE, Timmerman JM, Morrison SL. (2013) Anti-CD20-interferon-β fusion protein therapy of murine B cell lymphomas. Journal of Immunotherapy). 36(5):305-318.