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Published 23rd September, 2021
We hear from key experts across academia and industry about current approaches that are impacting the field.
Immuno-oncology, the approach of harnessing the body’s immune system to help fight cancer, has emerged in the last decade as one of the fastest-growing areas in cancer research. Recent successes in the use of immunotherapy to treat cancer, such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy, have provided breakthrough treatments for various refractory cancers. However, most patients either do not respond to immunotherapy or develop resistance, either primary or acquired, to treatment after a period of time, creating a key area of unmet medical need to understand and address1.
As part of our New Directions in Immuno-oncology: Response and Resistance online event, we hosted talks dedicated to the latest breakthroughs in cell therapies, including resistance to immunotherapies. These exciting discussions highlighted novel approaches to this issue from experts in the field, including:
The optimization of CAR-T cell technology and application of other immune cell types, such as NK cells, are helping to tackle the efficacy, cost, and logistical challenges of cell therapies for cancer2.
Here we feature key topics from our speakers and the promising new therapeutic avenues they are investigating.
Deregulation of the Hedgehog/Glioma-associated oncogene (Hh/GLI) signaling pathway is a powerful driver of tumor development, promoting numerous cancer hallmarks such as proliferation, survival, and metastasis. Hh/GLI signaling, unlike classical signaling cascades, is repressed in ligand absence and initiated by Hh ligand protein binding to its receptor, Patched (PTCH1)3. While several Hh pathway inhibitors have been approved, they do not have a high success rate.
Dr Maike de la Roche investigates Hh signaling pathways in immune cells, focusing on their role in effector and memory cell differentiation, maintenance, and function during infection, as well as tumor challenge.
“Cytotoxic T lymphocytes are functionally dependent on Hh signaling,” she explained. “CD8+ T cells are also the only lymphocyte population that is associated with good prognosis in nearly all human cancers, thus showing they have evolved a unique mode of Hh signaling. The signaling is entirely intracellular in the T cell and doesn’t depend on variable, exogenous ligand gradients.”
Dr de la Roche said this finding “might be an explanation as to why the Hedgehog inhibitors have failed in the clinic” and presents new therapeutic avenues to explore.
NK cells are critical immune components in controlling tumor growth and dissemination. NK-based therapies are actively pursued both pre-clinically and clinically because of their natural capability for eliminating tumor cells without prior sensitization. However, data suggests that tumors could polarize NK cells to tumor-promoting phenotypes by inducing functional alterations. This plasticity could result in undesirable outcomes for NK-cell-based therapies4.
Dr Uriel Moreno wants to understand the possible plasticity mechanisms within the tumor microenvironment through characterizing NK cell populations within human head and neck squamous cell carcinomas. Dr Moren identified several populations of NK cells in innate lymphoid cells (ILCs) within the tumor using single-cell RNA sequencing.
“The sequencing data revealed a spectrum of NK and ILC ‘states’ within the primary head and neck tumors, with ILC states being highly heterogeneous,” he explained. “Peripheral NK cells can acquire an ILC1 or tissue-resident phenotype in the tumor microenvironment, which can be recapitulated both in vivo and in vitro. Cells which have this phenotype and express CD49a appeared to have increased anti-tumor and effector functions.”
Immune checkpoint inhibitors are promising immunotherapy strategies, and the field is constantly evolving with novel T-cell immune checkpoint molecules constantly being discovered. Many of these emerging checkpoint targets are either in clinical trials or under active development5.
Dr Amir Horowitz aims to elucidate the mechanisms involved in tumor sensitivity by understanding the functional roles of human NK cells and CD8 T cells in microbial infections, cancer, and after transplantation.
“The role of NK cell receptors expressed on T cells as an emerging area of immunology that will hopefully explain the poor effectiveness of checkpoint blockade monotherapies, specifically monotherapies targeting PD-1,” Dr Amir Horowitz described. He went on to say, “combination strategies targeting PD-L1 and NKG2A might overcome some of the adaptive resistance displayed in current therapies.”
The challenges cancer researchers face in improving the efficacy of existing immunotherapies and developing new ones have enhanced the importance of understanding anti-cancer immune response mechanisms and the defects potentially responsible for the lack of this response in some cancer patients6.
Here we summarize some of the current areas being investigated as potential routes for overcoming resistance to immunotherapies.
Dr George Prendergast provided an update for the IDO field, which had previously suffered a failed trial. A recent discovery for this field, Dr Prendergast said, “are other enzymes that catabolize tryptophan that may contribute to cancer.” One such enzyme is TDO, he explained, “previously thought to only be involved in the metabolism of tryptophan in the liver, we now know is over-expressed in many cancers like IDO1.”
Going forwards, Dr Prendergast believes “many are thinking about combi-inhibitors that inhibit multiple enzymes,” which he thinks are going to be needed to “really get the most out of the IDO1, TDO, and IL4I1 blockade.”
Identifying resistance biomarkers is crucial to using immunotherapies effectively. Predictive biomarkers have the potential to guide treatment decisions by identifying patients who are unlikely to respond to certain treatments. These patients can then be directed toward alternative therapies to avoid potential toxicities7.
When discussing her work on predicting and identifying mechanisms of acquired resistance through testing markers in tissue samples from lung cancer patients, Dr Mari Mino-Kenudson stated, “the single-marker approach is inefficient for demonstrating their presence and special relationship.” Therefore, she said, “applying multiplex platforms that can maintain these unique relationships, such as multiplex immunofluorescence for small marker panels and digital spatial profiling (DSP) for large marker panels may be necessary.”
Dr Mino-Kenudson also discussed “genome-wide-scale CRISPR-Cas9 mutagenesis screens, single-cell RNA sequencing, and peripheral blood sample analysis” as emerging technologies that may help improve our understanding of the mechanisms of acquired resistance to immune checkpoint inhibitors. She stressed a profound understanding of the underlying biology of acquired resistance mechanisms is crucial to invent more effective immunotherapies.
Resistance to immunotherapies still presents a significant obstacle in patient response rates. However, the many promising, new avenues being investigated to understand the mechanisms of positive and negative cancer immune responses provide increasing hope for improved cancer treatments in the future.
All talks from the event, including those mentioned above, are available to watch on demand at a convenient time for you.
To help you consistently push the boundaries of what is achievable for future immuno-oncology tests, we have compiled a comprehensive selection of immuno-oncology tools and resources.
From target discovery to IVD or clinical phase analysis, find the support you need for every stage of your pipeline to get to market faster.