Download The 2016 AACR Annual Meeting Delivering Cures Through Cancer

Highlights from
The 2016 AACR Annual Meeting
Delivering Cures Through Cancer Science
Clarion attended this year’s AACR Annual Meeting, and highlight here some of the themes that emerged:
Every therapy is immunotherapy?
Immuno-oncology continues to dominate the excitement of the field. This year, there were over 1000
presentations or posters focused on cancer immunology or immunotherapy. Immune checkpoint inhibitors, such as
anti-PD1 and anti-PD-L1, remain the backbone agents of choice, as supported by new data including 5-year survival
data confirming the durability of anti-PD1 (nivolumab) responses in melanoma patients. However, there is mounting
evidence for other immunotherapy approaches: relieving T cell suppression (e.g., IDO1/TDO and adenosine
inhibitors), T cell co-stimulation (e.g., OX40 and GITR agonists), stimulatory cytokine signaling (e.g., IL-15 and STING
agonists), neoantigen vaccines, and modulating myeloid cells and macrophages (e.g., CSF1R inhibitors).
Furthermore, there is increasing recognition that radiation, cytotoxic chemotherapy, and numerous
molecularly targeted therapies not only target cancer cells directly, but also have immunomodulatory effects. For
example, this year’s meeting showed data that chemotherapy can upregulate PD-L1 expression, and featured a
numerous reports including a Major Symposium on potential synergies of combining radiation and immunotherapy.
It may go too far to say that radiation and chemotherapy should now be considered “immunotherapies”, as their
immunomodulation may be indirect (i.e., via effects on the cancer cell or the tumor microenvironment), but some
therapies may act directly on immune cells: PI3K-gamma inhibitors on tumor-associated macrophages, and BRAF/
MEK pathway inhibitors on T cells, modulating their trafficking into tumors. Regardless of how we label different
therapies, it’s clear that the biology of the cancer cell is intertwined with the biology of immune responses against
cancer. Greater integration of immunology with cancer biology is (at last) taking place, and promises to lead to
improved combination strategies—to achieve synergy and/or avoid antagonism.
The next wave of cancer therapies
Just a few years ago, immuno-oncology was one of many areas of active research and not the towering force
that it is today. What will the next wave of innovation be? The AACR plenary sessions suggest three possibilities.
The first possibility is to target epigenetic pathways: turning off master switches that regulate gene
expression in the cancer cell. At the opening plenary, Dr. James Bradner presented new evidence that bromodomain
inhibitors will be an important class of agents for treating cancers driven by the MYC gene—up to 20% of all cancers.
New science is also starting to point to rational combinations involving inhibitors of histone methyltransferases like
EZH2, as well as older agents like histone deacetylase (HDAC) inhibitors, and DNA methyltransferase (DNMT)
inhibitors—combinations with each other and with other treatment modalities including immunotherapy.
The second possibility is to target cancer metabolism: targeting specific metabolic pathways upon which a
cancer is dependent. At a plenary session dedicated to Metabolic Reprogramming, an Agios Pharmaceuticals
scientist reported that IDH inhibitors produced objective responses in 35–40% of IDH-mutant AML patients, about
half of those complete responses, providing support for this paradigm. However, as Dr. Craig Thompson presented in
that same session, cancer cells are metabolically adaptable and can switch between different sources of nutrients.
The success of metabolism-targeted therapies will also likely require combination approaches.
Finally, there may be new approaches to prevent cancer’s evolution of resistance to therapy. As Dr. Jeffrey
Engelman reviewed in a plenary session on Tumor Heterogeneity and Clonal Evolution, cancer may acquire
resistance in various ways, including secondary mutations in an oncogenic driver, bypass pathways, immune evasion,
or even transformation to a new type of cancer (e.g. from NSCLC to SCLC). New insights on cancer evolution may
lead to novel approaches to slow or prevent treatment resistance. For example, intermittent therapy may reduce the
selective pressure that drives evolution of resistant clones, and targeting enzymes like APOBEC may help prevent
cancers from mutating and acquiring the genetic variations required for evolution.
One Financial Center, Suite 1610 Boston MA 02111 Ph: 617.757.7850, www.clarionhealthcare.com
Sources: Abstr #CT001, CT096, CT099, SY12, 4364, CT097, SY39-02, 2654, CT137, SY03-01, 3208, 4898, SY31-02, 4702, 4705, 913, PL03-02, PL02-01, 877, 532, 3577
Highlights from
The 2016 AACR Annual Meeting
Delivering Cures Through Cancer Science
Innovations that enable innovation
Although the vast majority of presentations at the meeting focused on tumor biology and cancer therapies,
there were also discussions of innovative tools or approaches for accelerating the pace of cancer research.
CRISPR-based gene editing has already proven to be invaluable, and new work shows that additional gene
editing tools exist in the microbial world: researchers in the lab of Dr. Feng Zhang, one of the pioneers of CRISPRCas9 gene editing, have identified a novel enzyme, Cpf1, that can mediate gene editing in ways distinct from Cas9.
Molecular diagnostics continues to advance in several important ways. There are initiatives to build large
genomic and clinical datasets for researchers to analyze: AACR’s Project GENIE (Genomics, Evidence, Neoplasia,
Information, Exchange) and the government’s Precision Medicine Initiative reported progress building their datasets.
There is also an initiative to develop consensus on how to use PD-L1 as a predictive biomarker for anti-PD1/PD-L1
therapies: called the Blueprint Project, it engaged multiple companies to analyze and compare their PD-L1
companion diagnostic to others; initial results for NSCLC were presented at this meeting. However, it is unlikely that
a PD-L1 diagnostic will ever be completely predictive; multiple groups presented new evidence that automated,
digital analysis of multiplex immunohistochemistry provides better predictions than any one marker. A multifactorial
approach to immune biomarkers is essential, though the optimal approach has yet to be determined.
FDA initiatives also hold promise to accelerate how new drugs are developed. As Dr. Rick Pazdur mentioned
at the meeting, the FDA has recently endorsed and provided guidance on a “seamless” approach to oncology drug
development that is adaptive, fluid, and serves as an alternative to the traditional phase 1-2-3 sequence of trials.
“Moonshot” optimism—but a more challenging mission
This year’s AACR closing plenary session was historic in that it featured Vice President Joe Biden and the
Second Lady Dr. Jill Biden. The main focus of their visit was of course to promote and advance the National Cancer
Moonshot Initiative led by VP Biden. The “moonshot” metaphor reflects the unprecedented optimism in the cancer
research field today. It is still early in the immuno-oncology revolution, and yet the durable responses seen with
immune checkpoint inhibitors have fired our imaginations. Emerging science continues to teach us how to exploit
the weaknesses of cancer and how therapies may best be applied. Furthermore, like the Apollo missions, cancer
research is building upon decades of prior work. Although hundreds of thousands in the US still die from cancer
every year, the majority of patients diagnosed with cancer are cured through early detection and surgery, radiation,
combination chemotherapy, or other treatments. When immunotherapies and other new treatments further
diminish cancer’s lethality, they will be building on a strong legacy.
However, in other ways, the moonshot is a flawed metaphor for curing cancer. As Dr. William Kaelin from
Dana-Farber pointed out during a “Cancer Dialogue” session, it’s not just an engineering problem, it’s a science
problem. The physics that enabled the moon landing was well known by the 1960s; building and refining the
spacecraft was a task for engineers. The biology that underpins cancer is not fully understood and requires sustained
efforts in basic research. Furthermore, NASA’s moonshot just aimed to land a man on the moon—even once was
sufficient. Cancer will not be addressed through a one-time event: it is too heterogeneous, and it may arise in any of
us at any time, thus requiring constant vigilance. Curing cancer would be more akin to permanently colonizing all the
moons and planets of our solar system than merely landing on Earth’s moon.
VP Biden clearly recognized the challenge: his speech did not echo President Obama’s State of the Union
rhetoric to cure cancer “once and for all”, but rather set a more measured goal of making “10 years’ worth of
progress in 5 years”. Nevertheless, the initiative’s goals to lower hurdles for data sharing, increase and accelerate
research funding, and foster greater collaboration were warmly welcomed, and have the potential to make a
substantive difference to the lives of people with cancer.
One Financial Center, Suite 1610 Boston MA 02111 Ph: 617.757.7850, www.clarionhealthcare.com
Sources: Abstracts #71, 853; Prowell et al. (2016) NEJM DOI: 10.1056/NEJMp1603747; http://webcast.aacr.org/p/2016annual/932307