Over the week we will publish a blog mini-series of each day's key highlights from the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference (CICON17): Translating Science into Survival (September 6-9, 2017 in Mainz/Frankfurt, Germany), prepared by SMS-oncology's consultant Julia Holland, PhD.
Day 1: Neoantigens, Vaccines and Overcoming of Immunotherapy Resistance.
CICON’s first speaker Ton N. Schumacher from the Netherlands Cancer Institute elaborated on one of the currently most stunning aspects of cancer immunotherapies: The recognition of cancer neoantigens, tumor’s escape from immune surveillance and T cell exhaustion. He took us onto a journey from his recently published article (Mezzadra, Riccardo, et al. "Identification of CMTM6 and CMTM4 as PD-L1 protein regulators." Nature (2017)), which describes a new important regulator of PD-L1 expression, namely CMTM6. CMTM6 was found to be a key regulator of PD-L1 expression on a wide variety of cancer cells. The formerly uncharacterized protein tends to be associated with PD-L1 in a membrane complex formation and seems to be essential for the maintenance of PD-L1 on the cell surface.
CMTM6 was also the focus of a short talk by Marian Burr, a member of both the Peter MacCallum Cancer Centre in Melbourne, Australia and the Cambridge Institute for Medical Research, UK. Burr explained that CMTM6 modifies anti-tumor immunity in mice by regulating of constitutive and INF-gamma induced PD-L1 expression. Her team showed a protective function of CMTM6 against the degradation of surface PD-L1. This identifies CMTM6 as a potential novel target in the interplay of immune checkpoint cascade that offers new ways to overcome immune evasion mechanisms.
Besides the research on CMTM6, Schumacher’s team has developed a platform for an unbiased analysis of the intratumoral T cell receptor (TCR) repertoire in ovarian cancer (OVCA) and colorectal cancer (CRC) patients. It appears that the lack of intrinsic tumor reactivity in the majority of tumor infiltrating T cells (TILs) may limit the value of efforts to revert intratumoral T cell exhaustion. Therefore, they looked at the entire TCR repertoire of immune suppressed TILs to identify the small fraction of effective TCRs.
Source: Science Translational Medicine
His group is now capable to identify precisely these low tumor-reactive proportions of tumor reactive TILs in OVCA and CRC patients. This particular proportion of T cells recognizes only neo-epitopes that successfully can elicit an anti-cancer immune response against autologous tumor cells even though being in an immune exhausted state. Therefore, it is paramount that efforts to reengage T cells into the anti-tumor response should be focused more on these small proportions of exhausted, but capable T cells.
Improved ways for the identification and enhancement of the repertoire of tumor specific T cells in patients was also discussed by Stephen P. Schoenberger (La Jolla, CA, United States) and Catherine Wu (Harvard Medical School, Boston, MA, United States). Both stressed, that methods such as improved sorting and characterization of TILs for adoptive cell immunotherapy together with personalized approaches, including genome-mining and next-generation sequencing, might improve combination strategies, tailor-made for individual patients.
Ugur Sahin (founder of BioNTech) described in detail the production of individually tailored treatments based on RNA vaccines, which are being tested in the MERIT and LipoMERIT clinical trials. The variability of tumors and its unique antigen repertoire for each patient is an ongoing issue for cancer treatment. By sequencing the tumor upfront, RNA vaccines, can be personalized to fit the identified antigen repertoire of each single patient. In the MERIT trial, 5 out of 19 patients were reported to have an objective response with two patients experiencing complete response (CR) to the vaccine treatment alone, while one patient had CR after vaccine treatment in combination with anti-PD-1 checkpoint blockade. Importantly, vaccine-induced antigen spreading (an innate immune response against tumor epitopes that were not included in the given vaccination) was apparently observed in patients.
In the Lipo-MERIT trial - liposomal RNA vaccination (RNA-lipoplexes) is administered rather than intranodal vaccination of naked RNA. The difference lies in the systemic approach: the RNA is expected to be taken up by dendritic cells (DCs) in the lung and the vaccine peptides are produced, presented and distributed by these cells throughout the entire body via the lymph system, while intranodal injection locally addresses the DCs just in the vaccinated tumor draining lymph node. The first results of the trial are promising, with the induction of objective responses and the prevention of relapse in 8/11 disease free patients.
A new concept for neoantigen discovery was introduced by Céline Laumont (Institute for Research in Immunology and Cancer, Université de Montréal, Canada) who has developed a proteogenomic platform (using mass spectrometry and RNA sequencing) to predict tumor specific neo-antigens in cancer driven mutations originating from the non-coding regions of the genome. Peptides targeting these neoantigens were tested in mice, indicating that identification of neoantigens even from the vast range of non-coding sequences is possible.
Interested in more?
The next 2 blogs will cover the topics “Biomarkers, Novel Agents and Adoptive Cell Therapies” and “Combination Therapies, Checkpoint Inhibition and Resistance, Immunomodulators and Microbiota”. Interested? Follow us on LinkedIn to receive a notification or keep an eye on our website’s blog page.