A major contributor to the immune suppressive environment of tumors are the regulatory T (Treg) cells which inhibit the effector T cells that target the tumor cells. Eliminating these Treg cells will enable a stronger immune response against the tumor. Antibodies that target Treg cells specifically in the tumor represent an effective means to decrease Treg cell levels and to boost the tumor immune response.
Earlier research revealed that antibodies binding to CCR8 show good anti-tumor responses and immunological memory in preclinical tumor models (1, internal data). Moreover, there is ample evidence that CCR8 represents a good marker for tumor specific Treg cells across different cancer types, including breast, lung, colorectal and bladder cancer (2, 3, 4). In addition, there is a clear correlation between CCR8 expression levels on tumor Tregs and patient survival (2, 4) suggesting that these Tregs are potent suppressors of the anti-tumor immune response. Together, these data indicate that CCR8 is a preferred target to deplete the suppressive Treg cells specifically in the tumor.
For the of design of molecules depleting CCR8-expressing Tregs, Oncurious is using an antibody technology platform that has been validated over more than a decade for the generation of binders against GPCRs. In addition, Oncurious is generating further insights in the CCR8 biology at the tumor site, feeding into the selection of better CCR8 targeting molecules.
TB-403 is a therapeutic anti-placenta growth factor (PlGF) antibody being studied for the treatment of medulloblastoma, a rare and life-threatening brain tumor that mainly affects children. The safety of TB-403 has been previously studied in 70 adult cancer patients, showing that TB-403 was well tolerated.
A Phase 1 study has been initiated and follows the earlier announced partnership between Oncurious, its TB-403 project partner BioInvent, and the Neuroblastoma and Medulloblastoma Translational Research Consortium in the US. The study aims to recruit a minimum of 27 patients, with recruitment expected to be finalized end 2020.The final clinical study results are expected in 2021.
(1) Villarreal DO, L'Huillier A, Armington S, Mottershead C, Filippova EV, Coder BD, Petit RG, Princiotta MF. Targeting CCR8 Induces Protective Antitumor Immunity and Enhances Vaccine-Induced Responses in Colon Cancer. Cancer Res. 2018 Sep 15;78(18):5340-5348.
(2) Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, Chudakov DM, Rudensky AY. Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer. Immunity. 2016 Nov 15;45(5):1122-1134.
(3) De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, Bonnal RJP, Provasi E, Sarnicola ML, Panzeri I, Moro M, Crosti M, Mazzara S, Vaira V, Bosari S, Palleschi A, Santambrogio L, Bovo G, Zucchini N, Totis M, Gianotti L, Cesana G, Perego RA, Maroni N, Pisani Ceretti A, Opocher E, De Francesco R, Geginat J, Stunnenberg HG, Abrignani S, Pagani M. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity. 2016 Nov 15;45(5):1135-1147.
(4) Wang T, Zhou Q, Zeng H, Zhang H, Liu Z, Shao J, Wang Z, Xiong Y, Wang J, Bai Q, Xia Y, Wang Y, Liu L, Zhu Y, Xu L, Dai B, Guo J, Chang Y, Wang X, Xu J. CCR8 blockade primes anti-tumor immunity through intratumoral regulatory T cells destabilization in muscle-invasive bladder cancer. Cancer Immunol Immunother. 2020 Sep;69(9):1855-1867.