The proposed career development training plan will provide the candidate, Dr. Frederick Locke, with a pathway to independence as a researcher. Dr. Locke's long term career goals are to establish an active translational laboratory and a robust immunotherapy clinical trial program, investigating new strategies to promote T cell immune responses against multiple myeloma antigens. Dr. Locke's immediate goals are to develop expertise in clinical and translational investigation, acquire basic knowledge of tumor immunology, and cultivate skills in the design of innovative research strategies. The training plan includes didactic and practical experiences in each of these elements and is designed to capitalize on existing resources at Moffitt Cancer Center as well as the specific expertise of the mentors. The proposed research is a logical extension of Dr. Locke's preliminary data generated under the guidance of his mentor Dr. Claudio Anasetti. Survivin is a tumor associated antigen (TAA) linked to aggressive and progressive multiple myeloma (MM) and other cancers. A mutated full length survivin protein vaccine was created at Moffitt. Dr. Locke has demonstrated that the vaccine induces survivin specific immune responses, in vitro, against myeloma patients even when the survivin specific precursor frequency is very low. A novel vaccine schedule was identified by Dr. Locke, which in conjunction with autologous hematopoietic cell transplant, induces strong immune responses in myeloma patients.
Aim 1 will test such an approach against survivin. An alternative strategy to overcome tolerance to survivin is to expand survivin specific T effectors (Teff), which could be adoptively transferred to a myeloma patient to mediate tumor killing. Dr. Locke has reported that PTEN inhibition increases tumor killing activity of Teff. PTEN is a phosphatase that negatively regulates the PI3K/Akt axis important for both Teff anti-tumor immunity and inhibitory T regulatory cell (Treg) signaling. Without PTEN, Tregs are unable to inhibit the anti-tumor activity of Teffs.
Aim 2 will determine if commercially available PTEN inhibitors are able to enhance the expansion and function of survivin specific Teffs, while preventing the expansion of Tregs which could inhibit the anti-tumor immune response. The career development training plan will involve close mentoring by Dr. Claudio Anasetti, as well as oversight by an advisory committee. The co-mentor, Dr. Scott Antonia, will provide additional training in immunotherapy trial design and analysis. Key elements of the career development plan include: weekly interactions with Dr. Anasetti, classroom training in biostatistics and immunology, semi-annual meetings with the advisory committee, and regular seminars of the BMT, Immunology, and Myeloma Programs. It is anticipated that these experiences will lead to an R01 submission by the end of year 4 of the grant. Moffitt Cancer Center provides an ideal training environment for this opportunity. The training proposed in this K23 training grant will allow Dr. Locke to transition to an independent translational and clinical trial researcher.

Public Health Relevance

Multiple myeloma is an incurable cancer, and patients with tumors having detectable 'survivin', a tumor antigen, have a worse prognosis. I propose two investigations aimed at inducing T cell immune responses against survivin. First, I will conduct a clinical trial testing the ability of a unique vaccine against the full length survivin protein, usd in conjunction with high dose chemotherapy and autologous blood cell transplant, to induce immune responses in multiple myeloma patients. Second, I will grow in the test tube myeloma patients' T cells against survivin, with or without inhibitors of PTEN. PTEN is critical for T cell signaling and inhibiting it may improve the tumor killing ability of T cells, which could then be given back to patients as therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Subcommittee I - Transistion to Independence (NCI)
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Radaev, Sergei
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H. Lee Moffitt Cancer Center & Research Institute
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Locke, Frederick L; Anasetti, Claudio; Moffitt Immunotherapy Working Group and the Immune Cell Therapy (ICE-T) Program (2017) Transplanters drive CARs to the clinic by brewing ICE-T: the Moffitt roadmap. J Immunother Cancer 5:59