This is the second blog in a mini-series of key highlights from the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (September 6-9, 2017 in Mainz/Frankfurt, Germany), summarized by SMS-oncology's consultant Julia Holland, PhD.
Day 2: Biomarkers, Novel Agents and Adoptive Cell Therapies
The second day’s sessions started with the 2017 William B. Coley Lecture, given by Thomas Gajewski (University of Chicago, IL, United States), who will receive the 2017 William B. Coley Award for Distinguished Research in Basic and Tumor Immunology. Thomas Gajewski highlighted T cell infiltration, inflammation, and the expression of inhibitory immune checkpoints in relation to the concepts of “hot” and “cold tumors”.
The concept stems from the strength or level of immune infiltration and induced inflammation within the tumor tissue and whether the immune system is able to recognize and engage tumor cells. Hot tumors tend to have high infiltration and in several cancer indications this is a predictor of a potential better outcome for patients, especially in patients treated with checkpoint inhibitors.
In this context, Gajewski talked about his team’s research on anti-PD-1 immunotherapies and the understanding that their activity may be impeded by the actions of another immune checkpoint factor, namely IDO. A proof of concept phase I clinical trial tested the combination blockade of PD-1 and IDO. The promising results are now followed up in a phase III trial (Keynote-252/ECHO-301 trial, NCT02752074).
Along similar lines, he also discussed pre-clinical studies showing that the combination of LAG-3 (CD223) and 4-1BB (CD137) immunotherapies may be a promising way of targeting the vast majority of immune cells such as T and B cells, dendritic cells, natural killer cells, and macrophages.
The activation of 4-1BB by targeting antibodies is known to overcome immune tolerance of tumor antigens. This was also presented in a talk during the novel agent session by Ignacio Melero (Clinica Universidad de Navarra, Pamplona, Spain), who elaborated on testing such combinations in the clinic in combination with adoptive cell therapy in metastatic melanoma or with checkpoint inhibitors and chemotherapy.
The basic leucine zipper transcriptional factor ATF-like 3 (Batf3) was mentioned by several presenters as one of the new immunotherapy targets. Batf3 is a transcription factor responsible for the thymic differentiation process of dendritic cells that cross-present antigens to CD8 T-cells and produce interleukin-12 (IL12) in response to pathogens. These immune cells are crucial to the induction of an anti-tumoral T-cell response.
Several presenters discussed the use of biomarker strategies and new biomarker platforms in clinical trials involving immunotherapies. The focus lies on improvements in the characterization of tumor mutation burden and the corresponding tumor-infiltrating immune cell markers, as well as PD-L1 and gene expression profiles.
An interesting new approach for phenotyping of immune cell populations was presented by Niels Halama (German Cancer Research Center, Heidelberg, Germany), who is developing a visualization technique called MINOS (Multistage Image Analysis Workflow with Virtual Sections) for immune-related biomarkers in CRC. Using immunohistochemistry and image analysis, this new technique can track the localization, and quantify as well as characterize the phenotype of immune cells throughout sequential sections from a tumor biopsy.
Özlem Türeci (CI3, Mainz, Germany) introduced the concept of protein (BiMAB) and RNA (RiboMABs) based bi-specific single-chain antibodies that bridge T cells and cancer antigen CLDN6-expressing cancer cells. This engagement of the T cells by linkage to the tumor cells activates the T cell killing mechanisms that lead to elimination of advanced CLDN6+ tumors in mice. The usage of the RiboMAB format is expected to overcome some of the obstacles associated with protein production of bispecific antibody formats and improve their clinical applicability due to the fact that, the patient’s own cells will translate the RNA and produce the BiMABs.
A new format of TCR engineered T cells - TRuC™ (T Cell Receptor Fusion Constructs) - was introduced by Patrick Baeuerle (TCR2 Therapeutics Inc. Cambridge, MA, United States). This novel format of TCR engineered T cells outperforms the capacity of tumor elimination compared to CAR T cells and additionally induces lower levels of cytokines associated with several serious adverse events in clinical trials.
Adoptive Cell Therapies
Hyam I. Levitsky (Juno Therapeutics, Seattle, WS, United States) described how the company made sensitive quantification and repetitive pharmacokinetic analysis of CAR T cells possible while the cells are patrolling the patient’s body. They were looking for a minimally invasive method, thus the CAR T cells were engineered to express a PSMA related epitope which could be targeted by radionuclide PET imaging. This concept will soon be tested in the clinic. Another of Juno’s projects aims at linking individual TCRs sequences to the transcriptome (the genome wide RNA expression profile) across immune cell populations, tracking the fate and fitness of the TCRs, and defining a molecular basis for both factors.
Dirk Busch (Technical University Munich, Germany) gave a fascinating talk on the ability of longitudinal microscopy as a method for intravital (live) imaging of CAR T cells at work in primary CNV lymphomas in mice. The microsurgical preparation of a cranial window in mice allowed the intracranial injection of CAR T cells but also the live microscopic imaging of CAR T cells fighting and controlling the growth of large established CNS lymphomas. The imaging confirmed the capability of CAR T cells to intravasate into the blood stream and infiltrated draining and non-draining lymph nodes. Moreover, the same Anti-CD19 CAR T cells were given to a patient resulting in a CR in CNS Diffuse Large-B-Cell Lymphoma. It was possible to identify CAR T cells in the cerebrospinal fluid confirming the crossing of the blood-brain barrier. The ability of CAR T cells to re-expand in vivo months after the initial CAR T cell infusion at the time of tumor recurrence and the re-activation of these expanded CAR T cells was also confirmed for this patient.
Andrew Sikora’s (Baylor College of Medicine, Houston, Texas United States) work has shown that TGF-beta induces anti-tumor activities in Myeloid-Derived Suppressor Cells (MDSC) via the SMAD2 signaling pathway. MDSC developed in the presence of TGF-beta, showed a totally different (monocyte-like) phenotype compared to suppressive MDSC. He showed that intratumoral delivered MDSC matured in the presence of TGF-beta (given as an adoptive cell therapy) and in combination with radiotherapy increased significantly the anti-tumor activity and survival benefit in an HPV+ mouse tonsil epithelial cell (MTEC) tumor model. Similar effects of TGF-beta on human MDSCs development were also observed.
Stay tuned for the last part of the mini-series blog.