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AACR Meeting Opens With Focus on Liquid Biopsy, Immune Checkpoint Rx; Call for Interdisciplinary Research

CHICAGO (GenomeWeb) – The American Association for Cancer Research's annual meeting kicked off in Chicago on Sunday with a tribute to interdisciplinary research, as Chairwoman Elaine Mardis praised researchers from biological sciences, mathematics, engineering, computing, and other disciplines for working together over the past year to make discoveries to benefit patients.

New technology was certainly top of mind as University Cancer Center Hamburg researcher Klaus Pantel took the stage to talk about liquid biopsy technology and its possible clinical applications. Publications in the last 10 years about circulating tumor cells and circulating tumor DNA have risen tremendously, he said. CTCs can be used to diagnose disease, find hallmarks of metastasis, mark the progress of treatment, present patients with a prognosis, mark the chances of relapse, and to molecularly characterize certain cancers like gliomas, among other things.

The early detection of ctDNA, while still presenting a technical challenge, is also highly attractive  as a way to uncover disease much earlier, he added. The big problem now is that many liquid biopsy tests are only being clinically validated, but aren't being used in interventional clinical studies. The assays need to be validated by independent expert groups in to demonstrate their clinical utility, Pantel said.

He also pointed to the work of the Cancer-ID European consortium, which began in 2015, and is currently analyzing CTCs and ctDNA together in one liquid biopsy test, using a prediction of immune checkpoint therapy as a marker of success. Clinical trials are ongoing, but interventional trials must also be started, in order to go beyond whether such a combined test is merely clinical valid, Pantel said.

MD Anderson Cancer Center researcher Padmanee Sharma also spoke about a hot-button topic in cancer research today: immune checkpoint therapy. Specifically, she spoke about where the research in this area has gone since the breakthroughs of CTLA-4 blockade and PD-1/PD-L1 therapy.

CTLA-4 blockade is known to enhance tumor-specific immune response. Anti-CTLA-4 drugs opened a whole new field in cancer therapy. PD-1/PD-L1 therapies came along soon after, and now there are drugs that are approved to treat various cancers in this manner. Further, she said, research is showing that combination therapies are even more effective than monotherapies.

However, there are still key questions to answer, the most important of which is, why do some patients respond to therapy and others don't? The answers may lie in new targets that are currently being considered and researched.

In an ideal world, Sharma said, these targets would be studied in the lab, in cell lines and mouse models, with carefully considered hypotheses, before being moved to clinical trials. But things are moving much faster than that. There are currently more than 1,000 clinical trials being conducted on possible immune checkpoint blockade therapies. So in order to answer the questions that must be answered, lab and clinical research must be integrated, she said. The clinical trial paradigm must be redesigned in order for researchers to obtain appropriate samples for lab studies. She proposed adding Phase Ia and Phase IIa steps to the typical phases of the clinical trial in which patient tissues would be sent back to the lab in order for researchers to test for biomarkers that could be useful in testing for mechanisms of immune checkpoint blockade.

She also named several targets that need to be considered, such as ICOS, CD40, VISTA, CD47, and oncolytic viruses, noting that there are various clinical studies ongoing for each of these as possible therapeutic targets in various cancers.

Multiple immune checkpoints exist and are dynamic in their expression, she added, so they should be evaluated both in pre- and on-treatment human tumor samples to guide treatment decisions.

University of Lausanne researcher George Coukos spoke specifically about harnessing immunotherapy against ovarian cancer, which has proven to be difficult, as not all patients benefit from PD-1 blockade. His research seemed to harken back to Sharma's key question, and while his team has not yet found the answer, he said he and his colleagues have established a systems approach to interrogate the problem.

The system they have established includes human tumor histocultures, organoids, mouse models, clinical studies, automation, high-throughput data analysis, network biology, bioinformatics, and predictive modeling, among other approaches. "Predictive modeling for immune biology is really in its infancy today," Coukos said.

In Lausanne, he added, his team is developing an area near the university where researchers from various disciplines can work together for human tumor immunology discovery, to conduct integrated functional analysis, chemical and biological work, bioengineering, and "lots of bioinformatics," to curate, model, and interpret the data.

And finally, Charles Swanton of the Francis Crick Institute gave an update on the ongoing TRACERx (Tracking Cancer Evolution through Therapy) study, showing new data on cancer chromosome evolution in metastases in both lung and renal cancer patients.

Swanton last gave an update at the AACR annual meeting in 2016 in which he illustrated how the effort was illuminating the clonal evolution of lung cancer.

This year, he spoke about the researchers' efforts to quantify the chromosomal chaos that drives the evolution of mutations in both lung and renal cancer, noting that chromosomal instability is a driver of immune evasion.

He specifically presented new data on chromosomal instability and metastatic progression in renal cancer patients. The disease is characterized by an early loss of the 3p chromosome and mutations in VHL. Some patients have indolent disease, and some have aggressive disease. Until now, there have been no genomic biomarkers to help distinguish between these two cohorts of patients.

In the first 100 renal patients from the TRACERx study, the researchers found that intra-tumor heterogeneity and chromosomal complexity are both related to poor outcome. They sampled 1,200 biopsies from these 100 patients and found that increased chromosomal complexity was associated with metastatic progression. There were no mutational driver events, however.

A meta-analysis of three cohorts of patients also found that a loss of chromosomes 9p and 14q drove the disease, but again found that there were no mutational drivers, Swanton said. Loss of 9p was associated with poor overall survival outcome.

In closing, Mardis said, it is clear that through the convergence of data and expertise, "interdisciplinary science becomes more important as datasets become more complex," adding that the data produced by cancer researchers "belies the notion that one size fits all." She also noted the need for appropriate companion diagnostics to make sure that the right patients receive the benefit of important breakthroughs in precision medicine and targeted therapeutics.

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