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Personalized Combination Therapies Yield Better Cancer Outcomes

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Doctor consulting with patient
Credit: NIH National Cancer Institute Visuals Online/Daniel Sone

Gratifying progress has been made recently in an emerging area of cancer medicine called precision oncology. It’s a bold attempt to target treatment to the very genes and molecules driving a cancer, aiming to slow or even halt its growth. But there’s always more to learn. Now comes evidence that, while a single well-matched drug might be good, a tailored combination of drugs that attack a cancer in multiple ways at once might be even better.

The findings come from the I-PREDICT clinical trial, which treated people with advanced cancer who hadn’t benefited from previous therapy [1]. The NIH-funded team found that analyzing a tumor’s unique genetic and molecular profile provided enough information to recommend individualized combination therapies to patients. What’s more, patients who followed their individualized combination therapies most closely lived longer, with longer periods of progression-free disease, than did those who took fewer of the recommended drugs.

In most previous clinical trials of precision oncology, researchers have relied on a tumor’s unique profile to identify a single, well-matched drug to treat each patient. But cancer is complex, and, just as with certain infectious diseases, tumors commonly develop resistance to a single drug.

In the trial reported in Nature Medicine, researchers led by Razelle Kurzrock and Jason Sicklick, University of California, San Diego, wondered if they could improve treatment responses by tailoring combinations of cancer drugs to target as many molecular and genetic changes in a person’s cancer as possible.

To test the potential for this strategy to work, the researchers enrolled 83 people with various cancers that had advanced despite previous treatment. Tumor tissue from each patient was run through a comprehensive battery of tests, and researchers sequenced hundreds of genes to look for telltale alterations in their DNA.

They also looked for evidence that a cancer had defects affecting the DNA “mismatch repair” pathway, which causes some tumors to generate larger numbers of mutations than others. Mismatch repair defects have been shown to predict better responses to immunotherapies, which are designed to harness the immune system against cancer .

With all the data in hand, a special panel of oncologists, pharmacologists, cancer biologists, geneticists, surgeons, radiologists, pathologists, and bioinformatics experts consulted to arrive at the right customized combination of drugs for each patient.

The panel’s findings were presented to the health care team working with each patient. The physician for each patient then had the final decision on whether to recommend the treatment regimen, balancing the panel’s suggestions with other real-world factors, such as a patient’s insurance coverage, availability of drugs, and his or her treatment preference.

Ten patients decided to stick with unmatched treatment. But 73 participants received a customized combination therapy. As no two molecular profiles were identical, the customized treatment regimens varied from person to person.

Many people received designer drugs targeting particular genetic alterations. Some also received checkpoint inhibitor immunotherapies to unleash the immune system against cancer. Four people also were treated with hormone therapies in combination with molecularly targeted drugs. In all, most regimens combined two to five drugs to target each cancer profile.

Participants were followed until their cancer progressed, they could no longer take treatment, or they died. For each person, the researchers calculated a “matching score,” roughly defined as the number of molecular alterations matched to administered drug(s), with some further calculations.

The evidence showed that those with matching scores greater than 50 percent, meaning more than half of a tumor’s identified aberrations had been targeted, were more likely to have stopped the progression of their cancers. Importantly, half of patients with the higher matching scores had prolonged stable disease (six months or longer) or a complete or partial remission. Similar results were attained in only 22 percent of those with low or no matching scores.

These encouraging results suggest that customized combinations of targeted treatments will help to advance precision oncology. However, there are still many challenges. For example, many of the combinations used in the study have not yet been safety tested. The researchers managed the potential risk of toxicities by starting patients on an initial low dose and having their physicians follow them closely while the dose was increased to a level well-tolerated by each individual patient.

And indeed, they saw no evidence that those receiving a greater proportion of “matched” drugs (i.e. those with a higher matching score) were more likely to experience adverse effects than those who took fewer drugs. So, that’s an encouraging sign.

The researchers are now enrolling patients in a new version of the I-PREDICT trial. Unlike the initial plan, patients are now being enrolled prior to receiving any treatment for a recently diagnosed aggressive, often-lethal form of cancer. The hope is that treating patients with well-matched, multi-drug treatment combinations early will yield even better results than waiting until standard treatment has failed. If correct, it would mark significant progress in building the future of precision oncology.

Reference:

[1] Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, De P, Krie A, Piccioni DE, Miller VA, Ross JS, Benson A, Webster J, Stephens PJ, Lee JJ, Fanta PT, Lippman SM, Leyland-Jones B, Kurzrock R. Nat Med. 2019 Apr 22.

Links:

Precision Medicine in Cancer Treatment (National Cancer Institute/NIH)

Study of Molecular Profile-Related Evidence to Determine Individualized Therapy for Advanced or Poor Prognosis Cancers (I-PREDICT) (Clinicaltrials.gov)

Razelle Kurzrock (University of California, San Diego)

Jason Sicklick (University of California, San Diego)

NIH Support: National Cancer Institute


New Target for Cancer Immunotherapy: Exosomes

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It was once a central tenet of biology that RNA molecules did their work inside the cell. But it’s now clear that RNA molecules are also active outside the cell, with potentially major implications for our health. To learn more about these unrecognized roles, the NIH Common Fund has launched the Extracellular RNA (exRNA) Communication Program.

This month, members of this research consortium described their latest progress in unraveling the secrets of exRNA in a group of 18 papers in the Cell family of journals. And it’s not just RNA that the consortium is studying, it’s also proteins. Among the many exciting results just published is the serendipitous discovery that proteins carried inside tiny, bubble-like vesicles, called exosomes, may influence a cancer’s response to immunotherapy [1]. The work sheds light on why certain cancers are resistant to immunotherapy and points to new strategies for unleashing the immune system in the fight against cancer.

The new findings center on a type of immunotherapy drugs known as checkpoint inhibitors. They are monoclonal antibodies produced by industry that can boost the immune system’s ability to attack and treat cancer.

One of those antibodies specifically targets a protein, called PD-1, on the surface of certain immune cells. When PD-1 binds a similarly named protein, called PD-L1, on the surface of another cell, the interaction prevents immune cells from attacking. Some tumors seem to have learned this and load up on PD-L1 to evade the immune system.

That’s where checkpoint inhibitors come in. By blocking the interaction between PD-1 and PD-L1, the treatment removes a key check on the immune system, allowing certain immune cells to wake up and attack the tumor.

Checkpoint inhibitors work better in some cancer types than in others. In melanoma, for example, up to about 30 percent of patients respond to checkpoint inhibitor therapy. But in prostate cancer, response rates are in the single digits.

Researchers led by Robert Blelloch, a member of the exRNA consortium and a scientist at the University of California, San Francisco, wanted to know why. He and his team looked for clues in RNA within the cells taken from immunotherapy-resistant prostate cancers.

As published in Cell, the researchers got their first hint of something biologically intriguing in an apparent discrepancy in their data. As they expected from prior work, PD-L1 protein was present in the treatment-resistant cancers. But the PD-L1 messenger RNAs (mRNA), which serve as templates for producing the protein, told an unexpected story. The resistant cancer cells made far more PD-L1 mRNAs than needed to produce the modest levels of PD-L1 proteins detected inside the cells.

Where was the missing PD-L1? Blelloch’s team found it in exosomes. The cancer cells were packaging large quantities of the protein inside exosomes and secreting them out of the cell to other parts of the body.

In additional studies with a mouse model of prostate cancer, the researchers found that those PD-L1-packed exosomes travel through the blood and lymphatic systems to lymph nodes, the sites where immune cells become activated. Once there, PD-L1-laden exosomes put the immune system to sleep, preventing certain key cells from locating and attacking the cancer, including the primary tumor and places where it may have spread.

In important follow up studies, the researchers edited two genes in cancer cells to prevent them from producing exosomes. And, in the absence of exosomes, the cells no longer formed tumors. Importantly, both edited and unedited cells still produced PD-L1, but only those that exported PD-L1 in exosomes disarmed the immune system. Studies in a mouse model of immunotherapy-resistant colorectal cancer yielded similar results.

The new evidence suggests that blocking the release of PD-L1 in exosomes, even temporarily, might allow the immune system to launch a successful and sustained attack against a cancer.

Blelloch notes that many intriguing questions remain. For example, it’s not yet clear why antibodies that target PD-L1 on cancer cells don’t disable PD-L1 found in exosomes. The good news is that the new findings suggest it may be possible to find small molecules that do target PD-L1-packed exosomes, unleashing the immune system against cancers that don’t respond to existing checkpoint inhibitors. In fact, Blelloch’s team is already screening for small molecules that might fit the bill.

Since its launch about five years ago, the exRNA Communication Program has published an impressive 480 peer-reviewed papers, including the latest work in the Cell family of journals. I’d encourage readers to click on some of the other excellent work. I hear that another batch of papers will be published later this year.

Reference:

[1] Suppression of exosomal PD-L induces systemic anti-tumor immunity and memory. Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R. Cell. 2019 Apr 4;177(2):414-427.

Links:

Video: Unlocking the Mysteries of RNA Communication (Common Fund/NIH)

Immunotherapy to Treat Cancer (National Cancer Institute/NIH)

Blelloch Lab (University of California, San Francisco)

NIH Support: Common Fund; National Cancer Institute; National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse


Fighting Cancer with Natural Killer Cells

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GIF of immune cells attacking

Credit: Michele Ardolino, University of Ottawa, and Brian Weist, Gilead Sciences, Foster City, CA

Cancer immunotherapies, which enlist a patient’s own immune system to attack and shrink developing tumors, have come a long way in recent years, leading in some instances to dramatic cures of widely disseminated cancers. But, as this video highlights, new insights from immunology are still being revealed that may provide even greater therapeutic potential.

Our immune system comes equipped with all kinds of specialized cells, including the infection-controlling Natural Killer (NK) cells. The video shows an army of NK cells (green) attacking a tumor in a mouse (blood vessels, blue) treated with a well-established type of cancer immunotherapy known as a checkpoint inhibitor. What makes the video so interesting is that researchers didn’t think checkpoint inhibitors could activate NK cells.


Optimizing Radio-Immunotherapy for Cancer

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Zachary Morris

Zachary Morris
Credit: Alan Leon

Zachary Morris has certainly done some memorable things. As a Rhodes Scholar, he once attended an evening reception at Buckingham Palace, played a game of pick-up football with former President Bill Clinton, and traveled to South Africa to take a Robben Island Prison tour, led by the late Nelson Mandela. But something the young radiation oncologist did during his medical residency could prove even more momentous. He received a special opportunity from the American Board of Radiology to join others in studying how to pair radiation therapy with the emerging cancer treatment strategy of immunotherapy.

Morris’s studies in animals showed that the two treatments have a unique synergy, generating a sustained tumor-specific immune response that’s more potent than either therapy alone. But getting this combination therapy just right to optimize its cancer-fighting abilities remains complicated. Morris, now a researcher and clinician at the University of Wisconsin School of Medicine and Public Health, Madison, has received a 2017 NIH Director’s Early Independence Award to look deeper into this promising approach. He and his collaborators will use what they learn to better inform their future early stage clinical trials of radio-immunotherapy starting with melanoma, head and neck cancers, and neuroblastoma.


What a Year It Was! A Look Back at Research Progress in 2017

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I want to wish everyone a Happy New Year! Hope your 2018 is off to a great start.

Over the holidays, the journal Science published its annual, end-of-the-year list of research breakthroughs, from anthropology to zoology. I always look forward to seeing the list and reflecting on some of the stunning advances reported in the past 12 months. Last year was no exception. Science’s 2017 Breakthrough of the Year, as chosen by its editors, was in the field of astrophysics. Scientists were able to witness the effects of the collision of two neutron stars—large stars with collapsed inner cores—smacking into each other 130 million light years away. How cool is that!

Numbered prominently among the nine other breakthroughs were five from biomedicine: gene therapy, gene editing, cancer immunotherapy, cryo-EM, and biology preprints. All involved varying degrees of NIH support, and all drew great interest from readers. In fact, three of the top four vote-getters in the “People’s Choice” category came from biomedicine. That includes the People’s 2017 Breakthrough of the Year: gene therapy success. And so, in what has become a Director’s Blog tradition, I’ll kick off our new year of posts by taking a closer look at these biomedical breakthroughs—starting with the little girl in the collage above, and moving clockwise around the images:


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