Is Aspirin the New (Old) Immunotherapy?


Hello. I’m David Kerr, professor of cancer medicine from the University of Oxford.

For those of you who follow me on Medscape and WebMD, you know that I don’t like aspirin: I love it. I think it’s a wonderful drug. There’s a lot of work going on just now looking at its molecular pharmacology.

There’s a great recent paper published by Dr Tsuyoshi Hamada and colleagues[1] looking at the role of aspirin as an immune checkpoint blockade inhibitor. It’s a lovely study. Using part of a retrospective sample collection, they were able to look at the impact of post-primary treatment use of aspirin in patients with resectable colorectal cancer.

They hypothesized that patients who had tumors with low expression of programmed cell death ligand 1 (PD-L1) would be more sensitive to the beneficial effects of aspirin. They looked at just over 600 patients. [The study used] a beautiful statistical analysis that stratified [findings] and accounted for all of the other contributory factors that might be tied up with aspirin’s use: PIK3CA mutations, [CDX2 expression], and even tumor-infiltrating lymphocytes. It’s what you would expect from a research group of this quality. The analysis was done very carefully indeed.

At the end of the study, they showed that their hypothesis was correct. Patients with tumors with relatively low expression of PD-L1 (also known as CB274) did better than those patients who had tumors that expressed high levels of PD-L1, for which aspirin seemed to have no benefits at all.

This all fits in with the link-up between the prostaglandin E2 pathway and immune suppression. It suggests that aspirin may be yet another potential partner drug that may enhance the activity of the huge excitement around the drugs which block the PD-L1, PD-1, the whole immune checkpoint pathway just now.

It was a really nice, very carefully conducted study. The results were quite compelling in terms of the survival benefits accrued to postsurgical use of aspirin in patients with low levels of PD-L1 expression. It again shows the importance of the microenvironment in determining the outcome of tumor behavior. This gives some potential therapeutic insight into why aspirin might be a very useful companion drug to give in combination with these rather more expensive, more complex immune blockade inhibitors.

Aspirin wins again. There’s yet more plausible biological mechanism supporting its use.

 

For all book lovers please visit my friend’s website.
URL: http://www.romancewithbooks.com

A virus to be used as an effective immunotherapy in patients with brain cancer


https://speciality.medicaldialogues.in/a-virus-to-be-used-as-an-effective-immunotherapy-in-patients-with-brain-cancer/

Bill Gates Thinks Cancer Therapies Could Serve a Much Wider Purpose


IN BRIEF

During a recent keynote address, Bill Gates advocated the creation of a bridge between the private sector and global health, nothing that research conducted by the former could help treat the problems of the latter.

A WIN-WIN SCENARIO

Bill Gates has high hopes for the future of cancer research, and not just in the battle for which it’s intended. The philanthropist thinks the same therapies researchers are developing to fight cancer could one day be used to “control all infectious diseases.”

Gates made the claim during his keynote address at J.P. Morgan’s Annual Healthcare Conference in San Francisco. He told the audience that the immunotherapy used to treat cancer patients in the world’s more prosperous nations could eventually be used to control infectious diseases such as HIV, TB, and malaria in its poorest.

Unfortunately, according to Gates, the pharmaceutical and biotech companies conducting this research may not see any incentive to pursue such applications, but they should.

“[I]n health — as in many other aspects of life — the free market tends to work well for people who can pay…and not so well for people who can’t,” said Gates. “But over the last decade, our experience has shown that we can stretch the reach of market forces so the private sector’s most exciting innovations also benefit people with the most urgent needs.”

Gates told the audience that the private sector can benefit from achieving breakthroughs in global health, noting that developing economies are growing much faster than developed ones. Additionally, he believes the Gates Foundation can help mitigate any risk to the private sector by providing “more predictability” and by investing in companies with the technologies that could be useful for global health.

BEYOND CANCER

In 2016, an estimated 445,000 people died from malaria, 1 million from HIV-related illness, and 1.7 million from TB (including 0.4 million with HIV). If cancer treatments could prevent the spread of these diseases and help treat those already infected, we could see a significant decline in these figures.

But cancer research is just the start. As Gates said in his keynote, research to treat other health problems of “rich-world markets” could help doctors address the problems of poorer ones.

For example, research into neurodegenerative diseases such as Alzheimer’s could be useful for those trying to treat the hundreds of millions of children with cognitive development issues due to growing up in poverty. Meanwhile, researchers in Africa and South Asia attempting to address undernutrition may glean valuable insights from obesity research.

By creating a bridge between the private health sector in developed nations and the global health community, we can ensure that all the world’s citizens have access to the best treatment options available. As Gates concluded in his keynote, reaching this goal of health equity in our lifetime isn’t just a possibility — it’s an imperative.

Cracking Tumor Defiance


Why does immunotherapy achieve dramatic results in some cancer patients but fail in others?

Scientists have elucidated the mechanism behind some tumor’s ability to escape immunotherapy drugs.

Why does immunotherapy achieve dramatic results in some cancer patients but doesn’t help others? It is an urgent and vexing question for many cancer specialists.

Now, two research groups from Harvard Medical School based at Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.

The findings, the researchers say, reveal potential new drug targets and could aid efforts to extend the benefits of immunotherapy treatment to more patients and target additional types of cancer.

The discoveries are detailed in two articles published by the journal Science.

One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, comes from scientists at Dana-Farber and the Broad Institute of MIT and Harvard led by Eliezer Van Allen, HMS assistant professor of medicine at Dana-Farber and an associate member at the Broad, and Toni Choueiri, the HMS Jerome and Nancy Kohlberg Associate Professor of Medicine and director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The second report, which identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, HMS professor of neurology and director of Dana-Farber’s Center for Cancer Immunotherapy Research, and X. Shirley Liu of Dana-Farber.

The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodeling complex, is known as SWI/SNF. Its components are encoded by different genes, among them ARID2PBRM1 and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.

Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell carcinoma (ccRCC) gain clinical benefit—sometimes durable—from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.

The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive tumor antigens called, neoantigens, which help the patient’s immune system recognize and attack tumors and make the cancer cells’ microenvironment hospitable to tumor-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.

To search for other characteristics of ccRCC tumors that influence immunotherapy response or resistance, the researchers used whole exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analyzed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.

When the data were sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumors lacked a functioning PRBM1 gene. About 41 percent of patients with ccRCC kidney cancer have a nonfunctioning PBRM1 gene. That gene encodes a protein called BAF180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodeling complex.

Loss of the PBRM1 gene function caused the cancer cells to have increased expression of other genes, including those in the gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.

The finding does not directly lead to a test for immunotherapy response yet, the scientists caution, but they carry a clear therapeutic promise.

“We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations,” Choueiri said.

In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 tool to sift the genomes of melanoma cells for changes that made tumors resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.

The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodeling complex—the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells—as being involved in resistance to immune T cells.

When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon gamma produced by T cells and, in response, produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex—ARID2 and BRD7—are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors noted, “represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack.” Finding ways to alter those target molecules, they added, “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”

Research included in the report by Van Allen and Choueiri was supported by Bristol-Myers Squibb, American Association for Cancer Research Kure It Research Grant for Immunotherapy in Kidney Cancer, Kidney SPORE, and Cancer Immunologic Data Commons (National Institutes of Health grant U24CA224316).

Stomach Cancer: How Immunotherapy and Targeted Therapy are Changing Treatment


The approval of a targeted therapy and an immunotherapy drug for some patients with advanced stomach cancer reflects recent new approaches to this difficult-to-treat cancer that hasn’t had many therapeutic advances in recent years.

Stomach cancer, uncommon in the United States but a leading cause of cancer death globally, causes few definitive symptoms in early stages and is usually diagnosed too late for curative therapy. The main treatment for stomach cancer is surgery to remove the tumor, combined with chemotherapy, which can be given before or after surgery. Radiation therapy may also be used in combination with surgery or chemotherapy.

Investigators led by Dana-Farber's Adam Bass, MD, led to the identification of four subtypes of stomach cancers.

Unlike many other types of cancer, stomach cancer research has seen few developments leading to precision therapies that can home in on molecular weak points to halt or shrink tumors. One such therapy, approved in 2010, targets a protein, HER2, that is over-expressed on the surface of about 20 to 25 percent of stomach cancers. The drug trastuzumab (Herceptin) was approved for use with chemotherapy in patients with HER2-overexpressing metastatic cancer of the stomach or gastroesophageal junction – the area where the stomach and esophagus meet. Other drugs that target HER2, such as lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumab emtansine (Kadcyla), are now being studied in clinical trials.

Immunotherapy drugs, which help the patient’s immune system seek out and destroy tumor cells, have proven very effective for some patients with advanced melanoma, non-small cell lung cancer, kidney cancer, and other cancer types. In September 2017, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) for people with certain advanced cancers of the stomach or the gastroesophageal junction.

The approval applies to patients with advanced cancers, called adenocarcinomas, that have come back or continued to grow after having at least two previous treatments. The cancer cells must also test positive for the PD-L1 protein, which allows some cells to escape attack by the immune system. The FDA also approved a new lab test to check these cancers for the PD-L1 protein and determine whether the patient is likely to benefit from cancer drugs known as immune checkpoint inhibitors.

Pembrolizumab has also been approved to treat any type of tumor that is so-called MSI-High, meaning its cells exhibit microsatellite instability. A small percentage of stomach cancers have this characteristic.

In an effort to diagnose stomach cancer earlier, researchers are looking at known risk factors, such as mutations that run in certain families that increase the risk of the disease, although these are rare.

The strongest known risk factor for stomach cancer is infection with the H. pylori bacterium, which is found in about 50 percent of the world’s population. H. pylori infection causes chronic inflammation and increases the risk of developing ulcers and stomach cancer. However, most people whose stomachs harbor the bug don’t develop cancer.

Studies are being conducted to see whether antibiotic treatment of people who are chronically infected by H pylori will help prevent stomach cancer. Some studies have found that treating this infection may prevent precancerous stomach abnormalities, but more research is needed.

Another research effort, which has led to the identification of four subtypes of stomach cancers, highlights the complexity of the disease, and may eventually lead to more precise treatments. Investigators led by Adam Bass, MD, reported that analysis of 295 samples of stomach cancers revealed four groups that had distinct features and types of molecular alterations.

Bass, who directs the Center for Esophageal and Gastric Cancer at Dana-Farber, says that grouping the cancers this way will help researchers enroll patients in clinical trials that test drugs aimed at targeting their specific stomach cancer subtype.

Ovarian Cancer and Immunotherapy: An Update


Immunotherapy has revolutionized the treatment of many types of cancer and is now undergoing testing in ovarian cancer. Clinical trials of drugs known as immune checkpoint inhibitors, which can unleash a potent immune system attack on cancer cells, have produced remissions in about 10-15 percent of patients with advanced and recurrent ovarian cancer – somewhat of a respectable figure, but given these modest response rates, the side effects of these agents, and the sometimes short remission periods, new approaches for the use of these agents need to be explored.

Ursula Matulonis, MD, says this is a very exciting time in research into immunotherapy for ovarian cancer.

Perhaps one of the keys to achieving greater success with these agents is using them in combination with other therapies. Laboratory studies have provided an abundance of evidence that combinations of immunotherapy agents plus other biologic therapies may prove significantly more effective in ovarian cancer than immune checkpoint inhibitors alone.

Immune Checkpoint Inhibitors

Ovarian cancer is a heterogenous disease, firstly meaning that several different types, or “histologies,” exist, each with its own unique genetic make-up. It also means that within an individual patient, different sites of cancer are likely comprised of several, genetically distinct, subtypes of cancer cells. This is one reason why it can be so difficult to treat with chemotherapy or targeted therapies: while the drugs are lethal to some cancer cell subtypes, they may leave others largely untouched, allowing the surviving cells to grow and proliferate. Immune checkpoint inhibitors, by contrast, have the potential to eliminate a broader range of tumor cell subtypes, sharply reducing the potential for drug resistance.

One of the advantages of combination regimens is that the second drug has the potential to make tumor cells more vulnerable to the immune checkpoint inhibitor. Before such approaches can become standard therapy, however, a variety of questions need to be answered: Which combinations work best in individual tumors? Are combinations more effective as front-line or follow-up treatment? Is it possible to pre-select patients based on the specific genetic profile identified in the cancer, the number of prior therapies, the histology of the cancer, etc.? The number of potential combinations of checkpoint inhibitors and other treatments is rather large, so sorting out these questions will inevitably take time. But we’ve already made a great start.

Immunotherapy Clinical Trials

Recognizing the exceptional promise of immunotherapies for ovarian cancer, my colleagues and I in the Gynecology Oncology Program at Dana-Farber have made a concerted effort to lead and participate in clinical trials of immunotherapies in combination with other types of drugs. These drugs include targeted therapies, which block cancer-related proteins in tumor cells; PARP inhibitors, which interfere with tumor cells’ ability to repair certain types of DNA damage; standard chemotherapy agents; and anti-angiogenic drugs, which pinch off tumors’ access to circulating blood. More than half a dozen such trials are now open or are about to open. Most of these are phase 1 trials, small-enrollment trials that are primarily concerned with the safety of potential new treatments, but which also track their effectiveness. One of the trials is a phase 3 study, the final stage before a therapy can be submitted to the Food and Drug Administration for consideration as a standard therapy.

An array of other immunotherapy trials for ovarian cancer is in the planning stages in the Gynecologic Oncology Program. These include a trial of a “neoantigen vaccine,” a treatment designed to spur a powerful, very precise immune system attack on tumor cells, in patients already treated with chemotherapy. Another will investigate a combination of the checkpoint inhibitors tremelimumab, durvalumab, and radiation therapy.

In addition, several immunotherapy trials led by researchers within the Center for Immuno-Oncology at Dana-Farber are also open to patients with ovarian cancer and other gynecologic cancers. A full list of ovarian cancer treatment trials is available on the Dana-Farber website.

This is a very exciting time in research into immunotherapy for ovarian cancer. There’s every reason to expect that immunotherapy will prove as effective in the treatment of this disease as it already has in cancers such a melanoma, Hodgkin lymphoma, lung cancer, kidney cancer, and others. Today’s clinical trials are where the revolution in treatment will take place.

By Ursula Matulonis, MD, Director, Gynecologic Oncology, Susan F. Smith Center for Women’s Cancers.

Direct-to-brain chemo better than systemic drugs when immunotherapy is to follow


mouse brain
Mouse brain, coronal view.

Animal study suggests ‘best practice’ for preserving the immune system –

In experiments on mice with a form of aggressive brain cancer, Johns Hopkins researchers have shown that localized chemotherapy delivered directly to the brain rather than given systemically may be the best way to keep the immune system intact and strong when immunotherapy is also part of the treatment.

The researchers say their study results, reported in Science Translational Medicine, could directly affect the design of immunotherapy clinical trials and treatment strategies for people with a deadly form of brain cancer called glioblastoma.

“We understand that our research was done in a mouse model and not in humans, but our evidence is strong that systemic chemotherapy alters the immune system in a way that it never fully recovers,” says Michael Lim, MD, associate professor of neurosurgery and director of brain tumor immunotherapy at the Johns Hopkins University School of Medicine, and member of the Johns Hopkins Kimmel Cancer Center. “With aggressive cancers like glioblastoma, it is important that we don’t handicap the defenses we may need to add alternative treatments, such as immunotherapy, to chemotherapy,” he adds.

Lim’s laboratory in neurosurgery and a team from the Bloomberg~Kimmel Institute for Cancer Immunotherapy led by Drew Pardoll, MD, PhD, performed their studies in a mouse with glioblastoma. In people, glioblastoma is a particularly aggressive form of cancer, with a typical survival time of just over a year after diagnosis. Current treatments include surgical removal of the visible tumor, radiation and chemotherapy. Because the disease is so lethal, even after aggressive standard treatment, neurosurgeons like Lim are looking to add newer immunotherapies that use the body’s own immune system cells to fight the tumor.

However, one challenge to immunotherapy, Lim says, has been the potential toxic effects of systemic therapies that could damage or interfere with the immune system and weaken the chances for success of immunotherapy approaches. With clinical trials being designed to integrate standard of care with immunotherapy, Lim and his team sought to create a way to accurately assess the impact of localized versus systemic chemotherapy on the immune system’s ability to stay healthy, and to see which kind of chemotherapy would actually improve survival time in the test mice.

To determine if one method of chemotherapy delivery was better over another when combined with immunotherapy, the researchers first gave a group of mice with glioblastoma clinically relevant doses the immunotherapy drug anti-PD-1 (200 milligrams per kilogram) and then treated the mice with chemotherapy either throughout the whole body or directly to the brain over two weeks.

For the whole-body, or systemic, chemotherapy, the mice were injected in their bellies with 30 milligrams per kilogram of the chemotherapy drug carmustine—the same drug used against glioblastoma in people—three times a week. Each treatment group contained 15 mice. For the local chemotherapy, the researchers directly implanted a wafer covered in molecules that bound carmustine, allowing sustained release of the drug over a week, into mice with established brain tumors.

The researchers first took blood samples from the rodents’ lymph nodes, brain, bone marrow and blood a couple of days after the end of the chemotherapy treatments, almost two weeks later and at the four-month mark. They focused on counting the number of white blood cells (lymphocytes—T cells) as a way to measure immune system integrity. The mice given systemic chemotherapy had much lower levels of lymphocytes than the mice given the local, long-lasting chemotherapy. For example, two weeks after treatment, mice with systemic chemotherapy had only about a third of the lymphocytes in their circulating blood as mice given the local chemotherapy. The researchers say their findings align with what is observed clinically in patients who received systemic chemotherapy. Lim says the suppression is suggested that the lymphocyte depletion caused by systemic chemotherapy is likely counterproductive to producing an effective antitumor immune response.

Next, the team wanted to see if local versus systemic chemotherapy in conjunction with immunotherapy affected survival in the mice with glioblastoma. The scientists found that when they gave the mice chemotherapy locally, it acted together with the immunotherapy drug to improve survival to about 80 percent after 100 days when compared to mice receiving immunotherapy alone, local chemotherapy alone, or combined systemic chemotherapy and immunotherapy, with a survival rate of about 50 percent after 100 days. Then, they followed up these experiments by assessing the immune system’s memory. They gave mice local chemotherapy or systemic chemotherapy in conjunction with immunotherapy, and then implanted them with more tumors. The mice with the systemic chemotherapy and immunotherapy all died when injected with extra tumors. But the mice with local chemotherapy and immunotherapy survived, essentially immunized against their glioblastoma. The researchers say this suggests that the systemic chemotherapy profoundly weakens the immune system. The researchers showed that the immune system weakening phenomenon isn’t specific to carmustine and happens in multiple types of systemic chemotherapy, such as temozolomide.

The researchers also reversed the treatment protocols, giving the chemotherapy before the immunotherapy to see if that worked better and improved survival. They didn’t notice a difference in survival time whether the immunotherapy was given before or after the brain-specific chemotherapy.

Only 10 percent of people diagnosed with glioblastoma live more than five years, according to the American Brain Tumor Association. Glioblastoma mostly occurs in people over 45 and in men somewhat more often than in woman. An estimated 15 percent of the 78,000 people diagnosed with brain tumors in the U.S. each year will be diagnosed with glioblastoma.

Currently, a large number of immunotherapy trials are underway for patients with glioblastoma. There are only three immunotherapy drugs that are FDA-approved for treating other types of cancer, and they cost over $100,000 annually.

Molecular Imaging Tracks Lung Cancer Immunotherapy


Programmed death ligand (PD-L1) expression in tumors may predict response to checkpoint blockade therapy, but tissue samples are not always on hand to guide therapy. Imaging specialists have addressed this issue by developing and evaluating techniques for non-invasive imaging of PD-L1 expression in tumors.

“Non-invasive imaging of therapeutically effective PD-1 [programmed death 1] and PD-L1 antibodies is of high interest for preclinical and potentially also for the clinical development of these drugs, as it provides an elegant opportunity to obtain quantitative and kinetic information on the whole-body biodistribution of these antibodies, including parameters such as tumor accumulation and blood half-life,” explained Gabriele Niedermann, MD, PhD, of the German Cancer Research Center in Heidelburg, and colleagues, writing recently in Theranostics.

Niedermann’s group developed radiotracers, based on therapeutic checkpoint-blocking antibodies, that allowed for high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. This “immunoPET” of naïve mice showed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes).

The research also found that PD-L1 tracer uptake was reduced in PD-L1 knockout tumors, and that monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed “robust upregulation in the lung.”

“This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer,” Niedermann and colleagues wrote.

In another animal-model study, Samit Chatterjee, PhD, of Johns Hopkins University in Baltimore, and colleagues performed SPECT-CT imaging, biodistribution, and blocking studies in NSG (NOD scid gamma) mice bearing tumors with constitutive PD-L1 expression (CHO-PDL1) and in controls (CHO).

The preclinical evaluation of a humanized radiolabeled anti-PD-L1 antibody showed specific and increased uptake of radioligand in CHO tumors with stable PD-L1 expression compared with control CHO tumors. The results were confirmed in NSCLC xenografts with varying levels of PD-L1 expression, and in triple-negative breast cancer.

“Subcutaneous NSCLC xenografts showed specific uptake in H2444 tumors compared to H1155 tumors,” the researchers wrote.

They explained that the clinical utility of this antibody imaging agent and others would be to use the radiolabeled antibody accumulation in the tumors to guide therapeutic antibody dosing, and correlate that uptake with tumor response.

“This could be used to establish a relationship between tumor PD-L1 status and therapeutic response, which may have prognostic implications.”

Can these results be translated into humans? Yes, according to Jill Fredrickson, PhD, of Genentech in South San Francisco, and colleagues, who utilized FDG-PET-CT imaging to evaluate atezolizumab (Tecentriq) response among chemotherapy-naïve and previously treated stage IIIB/IV non-small cell lung cancer (NSCLC) patients.

Atezolizumab was developed by Roche, the owner of Genentech, and was grantedpriority review by the FDA in April 2016 for the treatment of locally advanced or metastatic NSCLC with PD-L1 expression.

Fredrickson’s group suggested that patients with NSCLC undergoing immunotherapy may benefit from FDG-PET imaging to assess their disease and predict treatment response, presenting the results of their multinational study at the 2016 Society of Nuclear Medicine and Molecular Imaging Annual Meeting.

Atezolizumab inhibits activity between the PD-1 receptor expressed on certain immune cells and PD-L1, leading to enhanced T-cell priming and re-invigoration of suppressed immune cells.

The primary endpoint of the phase II study was objective response rate on the basis of modified immune-related response criteria. Patients underwent single-time-point FDG-PET scanning — 60 minutes of radiotracer uptake prior to imaging — at baseline, at the time of first tumor assessment during week 6 of immunotherapy, and at disease progression.

Fredrickson and colleagues also wanted to determine if the PET modality and its FDG radiotracer could distinguish between radiographic pseudo progression — an increase in apparent tumor burden due to an anti-tumor T-cell response – from true disease progression.

The study enrolled 138 patients at 28 clinical sites in 5 countries, with 103 patients providing evaluable PET scans at baseline and a post-baseline time point. All patients received 1,200 mg of atezolizumab intravenously every 3 weeks. The scans were analyzed using European Organization for Research and Treatment of Cancer (EORTC) criteria.

Patients with metabolic response by EORTC criteria on scans at week 6 had a higher overall response rate (73.9%) than metabolic non-responders did (6.3%). A patient’s whole-body metabolic tumor volume at the FDG-PET baseline scan was found to be a significant negative prognostic maker for overall survival. A further increase of tumor volume at the 6-week scan was also a sign of decreased overall survival.

The researchers noted that response after apparent radiographic progression was seen in only two patients, so the utility of FDG-PET to distinguish pseudo from true progression could not be determined.

“The utility of FDG-PET in patients with NSCLC on immune blockade therapy appeared to be similar to what has been reported with conventional chemotherapeutic treatments, with early metabolic response predicting subsequent benefit,” the team concluded.

“This study is the first to prospectively evaluate FDG-PET imaging in a phase II trial of lung cancer patients receiving the novel immune checkpoint inhibitor atezolizumab,” Fredrickson said in a press statement. “These findings help define the potential role of FDG-PET as a prognostic and predictive biomarker in the treatment of lung cancer with such immunotherapeutics.”

ASCO names immunotherapy as cancer advance of the year


With the start of another year, the American Society of Clinical Oncology (ASCO) has announced the cancer advance of the year as the developments seen in immunotherapies.

Worldwide, there will be an estimated 22.2 million new cancer diagnoses by 2030, with a disproportionate number of cancer deaths in Central and Southeast Asia. [Stewart BW, Wild CP, World Cancer Report 2014] Despite the growing challenges to cancer care, breakthroughs in the development of immunotherapies demonstrate the continued efforts to improving patients’ lives.

“No recent cancer advance has been more transformative than immunotherapy. These new therapies are not only transforming patients’ lives, they are also opening intriguing avenues for further research,” said ASCO President Julie M. Vose. “Advances like these require bold ideas, dedication and investment in research. If we are to conquer cancer, we need to invest more as a nation to support a strong biomedical research enterprise.”

The call for immunotherapies as the advance of the year highlights the continued progresses with the immune checkpoint inhibitors ipilimumab, nivolumab and pembrolizumab. These drugs targeting CTLA-4 and the programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) proteins involved in the regulation of cell apoptosis have shown efficacy in advanced melanoma, extending patient survival from months to years with manageable adverse effects.
The past year saw evidence of PD-1/PD-L1 blockade in particular as an effective strategy in lung cancer as well. (See MIMS Onocology, “Pembrolizumab improves survival in PD-L1-positive advanced NSCLC patients“) This has led to the US FDA approvals of Bristol-Myers Squibb’s nivolumab and Merck Sharp & Dohme’s pembrolizumab for the treatment of advanced non-small-cell lung cancer (NSCLC) after failure of previous treatment.

Other immunotherapies in development include Roche’s atezolizumab, a PD-L1 inhibitor, which has received US FDA breakthrough designation for PD-L1-positive NSCLC and has shown additional success in a phase II study on advanced bladder cancer.

Ongoing studies looking at PD-1/PD-L1 inhibitors in kidney, liver, and head and neck cancers, and exciting evidence pointing to their potential in haematological malignancies (acute lymphoblastic leukaemia, diffuse large  B-cell lymphoma, Hodgkin’s lymphoma) and glioblastoma suggest that progress will continue to be seen in this area of research. Clinical trials evaluating combination strategies with immunotherapies are also underway.

In addition to the advances in immunotherapy, ASCO has highlighted the advances in precision medicine and cancer prevention for improving patient care and quality of life. As knowledge of tumour biology continues to grow, powerful new treatments that block specific molecules (eg, olaparib targeting PARP and palbociclib targeting cyclin-dependent kinases 4 and 6) or target genetic alterations (eg, KRAS-, EGFR- and ALK-targeted therapies) that fuel cancer growth are becoming standards of care for many cancers. These targeted approaches have also shown promise in some difficult-to-treat cancers of blood, ovaries, breast and kidneys.

Between October 2014 and October 2015, the US FDA approved 10 new cancer treatments, expanded the use of 12 previously approved cancer therapies and one device, and approved one new vaccine for the prevention of cervical and other cancers.
ASCO_fig1

As Vose emphasized, a critical component in the successes in cancer care is the availability of resources. “If we are to conquer cancer, we need to invest more as a nation so that we can prepare for what lies ahead,” she wrote. “Cancer care is set to change more dramatically in the next 20 years than it did in the last 50 years, thanks in part to advances in health information technology and a deeper understanding of cancer’s molecular drivers. As biomedical discovery expands, we need to be able to answer difficult questions and pursue new research directions.”

These new research directions include exploring new ways to improve patient outcomes by combining different immunotherapies, combining immunotherapies with traditional treatments such as chemotherapy, radiation therapy and surgery, and starting immunotherapy earlier in the course of disease. Researchers are also looking to identify biomarkers that can predict response to immunotherapy and guide treatment decisions.

“In the near future, cancer immunotherapy may become the fourth pillar of cancer treatment, along with chemotherapy, surgery and radiation therapy,” the report’s authors wrote.

Can We Treat Colorectal Cancer With Immunotherapy?


March is Colorectal Cancer Awareness Month. About 134,490 people are estimated to be diagnosed with and about 49,190 are expected to die from colorectal cancer in the United States this year. On this blog, you will find several posts that review the challenges and opportunities with screening for colorectal cancer, provide expert opinion on the progress made so far in addressing the challenges, and discuss new research and treatment options that signify progress being made against this disease.

In this post, let’s look at some recent studies that explore the possibility of using immunotherapy to treat colorectal cancer.

Immunotherapy approaches to treat cancers have, in recent years, yielded varying degrees of success. One factor that seems to influence the outcome is the immunogenicity of the cancers against which an immunotherapeutic is being tested. Immune checkpoint inhibitors, a type of immunotherapy, work by releasing the PD-1 “brake” present on T cells. By preventing the PD-1 protein from engaging PD-L1, a protein present mainly on tumor cells, these immunotherapeutics suppress the immune-inhibiting signals transmitted to T cells. The FDA has so far approved immune checkpoint inhibitors to treat certain melanomas, lung cancers, and kidney cancers.

But can we treat colon cancers with immune checkpoint inhibitors?

About five percent of all colorectal cancers are caused by a heritable mutation. Hereditary colorectal cancers, and about 15 percent of sporadic (nonhereditary) colorectal cancers, are known to have increased mutational load due to DNA mismatch-repair deficiencies. One hypothesis is that tumors that have a high mutational load are likely to be susceptible to immunotherapeutic targeting, because such tumors stimulate the immune system.

A paper and accompanying commentary published in Cancer Discovery last year explain how the immune microenvironment of colorectal cancers with microsatellite instability (MSI), a marker of mutations in DNA mismatch-repair genes, might make them good candidates for immune checkpoint inhibition. The study found that MSI tumors are highly infiltrated with activated CD8-positive cytotoxic T cell lymphocytes. However, MSI tumors also had high levels of inhibitory immune checkpoint proteins, including PD-1, PD-L1, CTLA-4, and LAG-3, which meant that the infiltrating immune cells were prevented from eliminating the tumors.

Micrograph showing tumor-infiltrating lymphocytes in a case of colorectal cancer with evidence of MSI-H on immunostaining.
Micrograph showing tumor-infiltrating lymphocytes in a case of colorectal cancer with evidence of MSI-H on immunostaining.

The immune checkpoint proteins found in MSI tumors described in theCancer Discovery paper—PD-1, PD-L1, CTLA-4, and LAG-3,—are all targets of immune checkpoint inhibitors being developed, tested, or that have been approved by the FDA. For example, pembrolizumab (Keytruda) and nivolumab (Opdivo) target PD-1, and ipilimumab (Yervoy) targets CTLA-4.

A multi-institutional team of investigators hypothesized that DNA mismatch repair–deficient tumors are likely to be more responsive to PD-1 blockade than tumors that do not have mismatch-repair deficiencies, and tested their hypothesis in a phase II clinical trial in a small group of patients. Results of this trial, published last year in The New England Journal of Medicine, proved their hypothesis right: Patients with mismatch repair-deficient colorectal cancer had better clinical response to PD-1 blockade by pembrolizumab than those whose colorectal cancers did not have mismatch-repair deficiencies.

A different approach

A study published in Clinical Cancer Research last week investigated an entirely different approach to making metastatic colorectal cancers responsive to immune checkpoint inhibitors.

In this study, a collaborative team of investigators from the University of Pittsburgh and the Soochow University in China found that a procedure used to treat liver metastases in patients with colorectal cancer, called radiofrequency ablation (RFA), could induce antitumor immune responses. They also found that mice treated with a combination of RFA and an immune checkpoint inhibitor survived longer than those treated with either one of the two therapies.

Binfeng Lu, PhD
Binfeng Lu, PhD

For patients with metastatic colorectal cancer, if liver metastasis is predominant and if the symptoms of their primary colon cancer are easy to manage, resection of liver metastasis prior to treating their colon cancer (liver-first approach) is considered the best option, explained study authorBinfeng Lu, PhD, an associate professor at the University of Pittsburgh. For these patients, RFA, a procedure that uses electrical energy to destroy cancer cells, is recommended as an alternative to surgery of the liver metastases, especially if the liver nodules are small.

Therefore, the researchers asked: can RFA make colorectal cancers immunogenic?

To find an answer to their question, Lu and colleagues analyzed colorectal tumor samples collected from a group of patients who received RFA of liver metastasis before their colorectal tumors were treated, and another group who had their colorectal cancers treated first.

The researchers found that in patients whose liver metastases were treated with RFA first, there was an increase in the infiltration of T cells in their colon tumors. They also found that these tumors had increased levels of the immune-inhibitory molecule PD-L1 in their tumor cells and in immune cells within the tumor.

“These properties of RFA suggest it can potentially be used to make colorectal cancer patients who are nonresponsive to PD-1-based immunotherapy become responsive,” Lu said.

The researchers then conducted experiments in mice and found that an anti-PD-1 antibody was effective in inhibiting the RFA-induced PD-L1 upregulation in mice bearing human colon tumors, and a combination of RFA and PD-1 blockade was more potent than RFA or PD-1 blockade tested individually. The investigators are planning to initiate a phase I clinical trial to evaluate whether combining RFA with an anti-PD-1 antibody immunotherapy will benefit patients with colorectal cancer who have liver metastases.

As surgical oncologist and immunotherapy expert Suzanne Topalian, MD,predicted in a blog post earlier this year, researchers continue to gain a lot more knowledge and a deeper understanding of how the immune pathways work so that immunotherapy can be extended to more cancer types.

The AACR is hosting a conference entitled “Colorectal Cancer: From Initiation to Outcomes” Sept. 17-20, 2016, in Tampa, Florida. The deadline to submit abstracts for this conference is July 11, 2016.