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MD Anderson Expanding 'APOLLO' Longitudinal Tumor Molecular Profiling Program

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NEW YORK (GenomeWeb) – Based on encouraging results from an initial pilot program in melanoma, the MD Anderson Cancer Center is expanding a longitudinal sampling and molecular analysis effort it calls APOLLO (Adaptive Patient-Oriented Longitudinal Learning and Optimization) to more than 2,000 patients with a variety of cancer types over the next two years.

The plan is to recruit patients enrolled in about 30 high-priority clinical trials under the umbrella of the center's Moon Shots program — a broad research effort aimed at dramatically reducing cancer deaths amongs a subset of 13 tumor types — offering them the opportunity to consent to participate in APOLLO, which involves analysis of multiple high-quality biopsies and blood samples, ideally before, during, and after a particular treatment.

Ignacio Wistuba, chair of the department of translational molecular pathology at MD Anderson, told GenomeWeb this week that the overall goal of APOLLO is to demonstrate that a longitudinal sampling approach — looking not just at tumors pre-treatment, but also during or after treatment — can uncover informative and hopefully clinically useful molecular or immunological information.

This could be either biomarkers that are predictive of patient outcomes on particular therapies, or a more general understanding of the molecular and biological underpinnings of acquired resistance and recurrence.

Wistuba said that the group is hoping to study patients enrolled in the "best trials" from within the Moon Shot effort, and in some tumor types outside of it. These will be trials "with an important clinical endpoint," he said, most of which are interventional, although some will be observational.

For each patient, the APOLLO team will take at least two or three tumor samples representing pre-treatment, on-treatment, and if a patient recurs, recurrence.

"We want to be able to say, looking at baseline samples, who are the most likely to recur, and in the recurrence samples what are the mechanisms that led to that," Wistuba said.

Samples will first be analyzed for whatever particular biomarker is of relevance to the Moon Shot or other clinical trial that that patient is enrolled in, and then will be subject to comprehensive whole-exome sequencing, RNA-seq, and immune profiling.

Providing rationale for the newly announced expansion of APOLLO, researchers from the project published data earlier this year from a smaller pilot phase of the project in which they performed immune profiling of both pre- and multiple post-treatment biopsy samples from melanoma patients treated with two immunotherapeutic drugs.

In that study, reported in Cancer Discovery online in June and in print this month, the team analyzed biopsies using both a 12-marker immunohistochemistry panel and a custom 795-gene NanoString panel. In on-treatment samples, the group was able to identify multiple gene expression and immune biomarkers that distinguished responders versus non-responders to anti-PD-1 treatment, including a higher ratio of CD8+ T cells at the tumor center versus the margin within responders compared to nonresponders.

In contrast, profiling of pretreatment samples largely failed to predict patients' clinical responses

In a commentary appearing alongside the study in this month's issue of Cancer Discovery, Michele Teng, Rajiv Khanna, and Mark Smyth of the QIMR Berghofer Medical Research Institute in Australia, wrote that the data suggest that "assessment of adaptive immune responses via early on-treatment biopsies should be considered as well as, or in place of, pretreatment biopsies to predict patients who will respond to anti–PD-1 treatment."

According to the Australian commentators, it will be important moving forward to set up larger cohort studies to determine how early immune signatures of response can be observed, to potentially allow for early intervention in nonresponders with other drugs or treatment strategies.

Wistuba said that it is possible that APOLLO could uncover similar on-treatment biomarkers that predict response and outcomes for the other cancer types it is now expanding to, with the potential to guide decisions about whether to continue to treat a patient with a drug or move them to another option with better likelihood of response.

If the investigators don't find these types of predictive biomarkers, the effort could still prove valuable by offering molecular insight into the development of treatment resistance, or the nature of tumors that appear to respond to treatment only to recur much later.

Alongside multiple tissue samples, APOLLO will also collect multiple blood samples from participating patients, to study them in the context of the findings from comprehensive molecular profiling of matched tissue samples.

If the longitudinal tissue samples reveal important genomic or immune biomarkers of response, researchers can then also seek these out in the blood samples, as a way of exploring the potential for future liquid biopsy strategies that would preclude the need for multiple on-treatment tissue biopsies.

"We think we can learn more from the tissue and then take some of the markers to an easier sample like blood," Wistuba explained.

Both the overall longitudinal sampling philosophy of APOLLO, and its potential to advance liquid biopsy approaches reflect a growing movement in the cancer diagnostics space, with other groups also pursuing studies that use either tissue or blood-based biopsies at multiple time points to aid understanding of disease heterogeneity and the development of resistance.

One of these, a study called TRACERx (Tracking Cancer Evolution through Therapy), is also collecting multiple tumor tissue samples and blood samples, in this case specifically from patients with non-small cell lung cancer.

Researchers from the study presented data earlier this year at the annual meeting of the American Society of Clinical Oncology, illustrating how the effort is illuminating the clonal evolution of the disease in new ways.

According to Wistuba, the APOLLO effort is gearing up for its planned expansion now with the goal of sampling at least 2,000 patients over the next two years, and with hopes of "expanding significantly in the next five years."

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