To identify new antigens that are targets for the immunotherapy of prostate and breast cancer, we used expressed sequence tag and genomic databases and discovered POTE, a new primate-specific gene family. Each POTE gene encodes a protein that contains three domains, although the proteins vary greatly in size. The NH 2 -terminal domain is novel and has properties of an extracellular domain but does not contain a signal sequence. The second and third domains are rich in ankyrin repeats and spectrin-like helices, respectively. The protein encoded by POTE-21, the first family member discovered, is localized on the plasma membrane of the cell. In humans, 13 highly homologous paralogs are dispersed among eight chromosomes. The expression of POTE genes in normal tissues is restricted to prostate, ovary, testis, and placenta. A survey of several cancer samples showed that POTE was expressed in 6 of 6 prostate, 12 of 13 breast, 5 of 5 colon, 5 of 6 lung, and 4 of 5 ovarian cancers. To determine the relative expression of each POTE paralog in cancer and normal samples, we employed a PCR-based cloning and analysis method. We found that POTE-2A, POTE-2B, POTE-2;, and POTE-22 are predominantly expressed in cancers whereas POTE expression in normal tissues is somewhat more diverse. Because POTE is primate specific and is expressed in testis and many cancers but only in a few normal tissues, we conclude POTE is a new primate-specific member of the cancer-testis antigen family. It is likely that POTE has a unique role in primate biology. (Cancer Res 2006; 66(1): 52-6)

Expression of SH 2 -homology-containing protein-tyrosine phosphatase-1 (SHP-1), a candidate tumor suppressor, is repressed in human T-cell leukemia virus type-1 (HTLV-1)-transformed lymphocyte cell lines, adult T-cell leukemia (ATL) cells, and in other hematologic malignancies. However, the mechanisms underlying regulation and repression of SHP-1 remain unclear. Herein, we cloned the putative full-length, hematopoietic cellspecific SHP-1 P2 promoter and identified the "core" promoter regions. HTLV-1 Tax profoundly represses P2 promoter activity and histone deacetylase-1 (HDAC1) potentiates such inhibition. NF-B was implicated as both a rate-limiting factor for basal P2 promoter activity and important for Tax IntroductionAdult T-cell leukemia (ATL) is an aggressive malignancy of CD4 ϩ , CD25 ϩ T cells, and the human T-cell leukemia virus type-1 (HTLV-1) has been identified as the causative agent. 1,2 While the understanding of ATL pathogenesis currently remains incomplete, the HTLV-1 virusencoded Tax protein has been implicated as a major contributor in the development of ATL. [3][4][5][6] The oncogenic potential of HTLV-1 Tax has been associated with its ability to modulate expression and function of cellular targets involved in cell proliferation and differentiation. 7,8 For example, Tax has been shown to induce the activation of NF-B, CREB, AP-1, and SRF 6 as well as to up-regulate IL-2/IL-2 receptor-␣, 9 IL-15, 10 IL-4, 11 12 and OX40/OX40L 6 pathways, resulting in the stimulation of cell growth. Tax can also be a negative regulator of gene expression/function and can down-regulate expression of genes involved in host DNA repair, 13 maintaining genetic stability 14 and cell cycle progression. 15 Of particular importance to this study, Tax has been shown to exert negative effects on at least 3 cellular tumor suppressorsRb, [16][17][18][19] hDLG, a human homolog of the Drosophila discs large tumor suppressor protein, 6,20-22 and p53. 6,23,24 Tax alone is able to immortalize primary human T lymphocytes and transform rodent fibroblast in vitro. 25,26 Transgenic mice expressing Tax can also develop tumor in vivo with a wide range of phenotypes . 25,27,28 Among the cellular dysfunctions caused by HTLV-1 infection, the loss of IL-2 dependence is remarkable in many HTLV-1-transformed cells. 29 In HTLV-1-infected cord blood lymphocytes, the transition from IL-2-dependent to IL-2-independent growth has been shown to correlate with the acquisition of a constitutively activated Jak/STAT pathway, suggesting the involvement of this pathway in HTLV-1-mediated T-cell transformation. 30 In addition, proliferation of uncultured leukemic cells from ATL patients has been reported to be associated with constitutive activation of Jak/STAT proteins. 31 A number of cellular factors have been demonstrated to negatively regulate Jak/STAT activities, including SHP-1 (SH2-homology-containing protein-tyrosine phosphatase-1), PIAS-3 (protein inhibitors of activated STATs), SOCS-1 (suppressors of cytokine signaling), and CIS (cytokine-in...

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TPS4599 Background: The majority of non- prostate genitourinary (GU) cancers are lethal when metastatic and rare GU cancers have limited treatment options. Bintrafusp alfa is a bifunctional fusion protein composed of human TGF-β receptor II, which sequesters or “traps” all three TGF-β isoforms and a monoclonal PD-L1 antibody. NHS-IL12 is an immunocytokine composed of two IL-12 heterodimers, each fused to the H-chain of the NHS76 antibody. The NHS76 IgG1 antibody has affinity for both single- and double-stranded DNA (dsDNA) allowing for targeted delivery of pro-inflammatory cytokine, IL-12, to necrotic portions of tumor with DNA exposure to promote local immunomodulation. Preclinical data suggest synergy between these two agents. There is also evidence suggesting that stereotactic body radiation therapy (SBRT) can promote anti-tumor immune responses both locally and systemically while also synergizing with immune checkpoint inhibitors. Therefore, the combination of Bintrafusp alfa, NHS-IL12 and radiation is a potential strategy for metastatic non-prostate GU tumors. Methods: This is an open label, non-randomized, three-stage phase I trial of bintrafusp alfa and NHS-IL12 or bintrafusp alfa and NHS-IL12 in combination with either sequential or concurrent SBRT. Bintrafusp alfa (IV 1200 mg q2w) and SBRT (8 Gy x 3 fractions) are planned with a deescalating NHS-IL12 (subQ q4w) dose schedule. The accrual ceiling has been set at 66 patients. The trial will enroll patients with a pathologically confirmed diagnosis of metastatic non-prostate genitourinary cancer with an ECOG ≤ 2 (KPS ≥60%). Participants may have had prior cancer immunotherapy but excluding prior treatment with bintrafusp alfa and/or NHS-IL12. 9 patients will receive treatment in cycles consisting of 4 weeks. The primary objective is to determine the safety and highest tolerated doses with acceptable toxicity (recommended phase II dose) of bintrafusp alfa and NHS-IL12 alone or in combination with SBRT administered sequentially or concurrently in patients with metastatic non-prostate genitourinary cancers. Secondary objectives are objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Exploratory objectives are to determine peripheral immune modulation and the status of the immune microenvironment using cytokine analysis, circulating tumor cells, multiplex immunohistochemistry, T-cell receptor sequencing, and RNA-sequencing. The study is open and enrolling. Clinical trial information: NCT04235777.