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Gilboa lab

Cancer immunotherapy

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Investigator / Contact Person Eli Gilboa

Research

Immune therapy is emerging as a promising therapeutic modality for cancer patients underscored by the recent FDA approval of two immune acting drugs for melanoma and prostate cancer. Nonetheless, the therapeutic benefit of the drugs was modest, stressing the need to develop more potent and/or complementary treatments. Dr. Gilboa’s cancer immunotherapy program is guided by three requisites that are paramount to the development of successful treatments for cancer. First and foremost, absent a “magic bullet” to treat cancer, we need to develop a combination approach of complementary and synergistic treatments. Second, need to pay attention to the feasibility of the therapy, from the standpoint of cost, complexity, and/or access to the drug. Third, arguably a main challenge in clinical oncology, need to address the dose-limiting toxicity of cancer drugs, including immune modulatory drugs.

Addressing feasibility, they are developing a new platform for drug and drug delivery consisting of short forms of nucleic acids, oligonucleotides (ODNs) that offer significant advantages in terms of feasibility and cost. The toxicity issue – the key aspect of our program – is addressed by targeting the ODN-based drugs, e.g., siRNAs, microRNAs, to the appropriate cells in vivo, the tumor and/or the immune cell, in effect converting poorly-specific, and even nonspecific, drugs into a specific outcome. The targeting ligands consist are ODN aptamers that exhibit specificity and avidity that is comparable and often exceeds that of antibodies.

Using the aptamer-targeted RNA therapeutics platform, we are developing a combination of novel and unique, as well as clinically useful and broadly applicable, approaches with complementary and synergistic mode of action to enhance the immune susceptibility of the disseminated metastatic tumor lesions of the cancer patient. Targeting tumor cells, They have developed a new paradigm in cancer immunotherapy (15) whereby new antigens, neoantigens, are expressed in tumor lesions, in effect making the tumor more “visible” to the immune system. Absence or reduced numbers of neoantigens in the patient’ tumor lesions was recently shown to be a major impediment to successful immune therapy. Given the ability to express new antigens in tumor cells in situ, They are exploring ways to vaccinate against future tumors for patients in remission to prevent recurrence and for individuals at high risk of developing cancer whereby subjects are first vaccinated to induce immune responses against said neoantigens and if or when a tumor develops induce the same antigens in the tumor. Dr. Gilboa’s team have also used the aptamer platform to target immune modulation to tumor lesion as a way of reducing associated toxicities as seen in patients undergoing checkpoint blockade therapy (17, 18) and enhance the persistence of the vaccine-induced immune response (13, 19). A most recent approach they are developing is to enhance the uptake of tumor antigens by the professional antigen presenting system, the dendritic cells, by coating the tumor cells in situ with pre-existing polyclonal antibodies that are recruited to the tumor by aptamer targeted antigens/hapten-specific to either vaccine-induced or naturally occurring antibodies.

Applications of aptamer-targeted nucleic acid therapeutics for immune manipulation, separately and/or in combination, have reached the cusp of clinical testing – a main challenge and current focus their program. The animal studies, having provided strong foundation for the feasibility and efficacy of this new platform, suggest that phase II indication-to-efficacy clinical trials, especially when using a judicious combination of two of the above strategies, could exhibit unprecedented therapeutic benefits in cancer patients.