Expanding Use and Refining Patient Selection

Cancer cell and T cell illustration
Fig. 2: When a cancer cell encounters a T cell (a type of immune cell), the interaction between the major histocompatibility complex (MHC) and the T-cell receptor (TCR) molecules activates the T cell. But when the PD-L1 checkpoint protein on the cancer cell attaches to the PD-1 checkpoint receptor on the T cell, the T cell is deactivated. 

This year, ASCO has named Immunotherapy 2.0 as the advance of the year. This selection recognizes the growing wave of progress using cancer immunotherapy, which has extended and improved the lives of patients, many of whom had few other effective treatment options.

It has taken scientists more than a century to learn how to harness the immune system to fight cancer. A number of strategies to achieve this have been tried, but one approach—blocking immune checkpoints—has been particularly effective against a range of different cancers. Immune checkpoints are specialized proteins that act as brakes on the immune system, ensuring that immune defenses are engaged only when they are needed and for as long as they are needed. They prevent the immune system from becoming overactive, which can lead to excessive inflammation or autoimmune disease.

Cancer treatments known as immune checkpoint inhibitors unleash the immune system to attack cancer (Fig 2a, Fig 2b). Since the first remarkable reports of immune checkpoint inhibitors shrinking advanced melanoma in 2011, research in this area has taken off at an incredible pace. Over the past year, the FDA approved five new uses for immune checkpoint inhibitors: lung cancer, head and neck cancer, bladder cancer, kidney cancer, and Hodgkin lymphoma. However, many other patients with the same types of cancer either do not benefit from immunotherapy at all or experience a benefit that is short lived. New research reported in 2016 is advancing the ability to identify patients who  are most likely to benefit from immunotherapy, while sparing others from its high cost and  adverse effects.

Cancer cell and T cell illustration
Fig. 2b: New immune checkpoint inhibitor therapies prevent the PD-L1 checkpoint protein from attaching to the PD-1 checkpoint receptor. This allows the MHC and TCR interaction to activate the T cell and unleash the immune system to attack cancer.

Progress with Immune Checkpoint Inhibitors

Immunotherapy extends long-term survival in advanced melanoma.

The number of people diagnosed with melanoma has risen sharply over the last three decades and is continuing to increase worldwide. In 2016, an estimated 76,380 adults in the United States were diagnosed with melanoma of the skin.1 Melanoma is the fifth most common cancer among men and the seventh most common cancer among women.

Although it accounts for only 1% of all skin cancers, melanoma causes the vast majority of deaths resulting from skin cancer. It is estimated that 10,130 deaths resulting from melanoma occurred last year.1

Most people with melanoma are cured with surgery alone. However, among patients with metastatic melanoma, only 17% will live 5 years after their diagnosis.

In just a few short years, immunotherapy has transformed the outlook for this disease. Given the lasting responses seen in a large proportion of patients who have received immunotherapy, experts are beginning to speculate that a cure may be within reach, at least for a fortunate few patients.

Approval of the checkpoint inhibitor ipilimumab marked the first treatment that could prolong life for patients with advanced melanoma (ipilimumab blocks the immune checkpoint cytotoxic T-cell lymphocyte-4 [CTLA-4]). By the end of 2014, the FDA had approved two additional checkpoint inhibitors for use in patients with advanced melanoma: pembrolizumab and nivolumab. In research studies, both proved to be even more effective than ipilimumab, while causing fewer adverse effects.

In 2016, researchers reported findings from the long-term follow-up of 655 patients enrolled in an early clinical trial of pembrolizumab.2 The median survival was 23 months, and the 24-month survival rate was 49%. Tumors shrunk in one-third of the patients, and treatment responses lasted more than 1 year in 44%. Pembrolizumab was generally well tolerated, with severe adverse effects occurring in only 14% of patients. The most common adverse effects included fatigue, itchiness, and rash.

The findings are similar to those previously reported for nivolumab, which yielded a 24-month survival rate of 43% among patients with advanced melanoma.3 By comparison, an earlier analysis of pooled data from several trials of ipilimumab found a median survival of only 11.4 months.4 Ongoing studies are exploring combinations of different checkpoint inhibitors, which seem to work better than one checkpoint inhibitor alone, although they produce more adverse effects.5

Meanwhile, a large clinical trial found that adjuvant immunotherapy can also help extend life for patients who have stage III melanomas that can be surgically removed.6 Despite successful surgery, a majority (approximately 60%) of such patients will experience a recurrence of melanoma within 4 years of removal. In the study, patients who had undergone surgery that completely removed the cancer were randomly assigned to receive ipilimumab or placebo. The 5-year survival rate was 65% in the ipilimumab group and 54% in the placebo group. Immunotherapy helped reduce the recurrence of melanoma and metastasis (i.e., spreading to distant parts of the body). At 5 years, more patients in the ipilimumab group had not yet experienced a recurrence (41% v 30%) or metastasis (48% v 39%).

Of note, the dose of ipilimumab was approximately three times higher than the  FDA-approved dose for this patient population (10 mg/kg v 3 mg/kg). This higher dose was chosen on the basis of earlier research showing that the higher dose may be more effective, although it does result in more adverse effects. In this study, 54% of patients experienced a severe adverse effect, and five (1%) died as a result of treatment-related adverse effects.

These findings suggest that high-dose ipilimumab may help patients with stage III melanoma live longer after surgery. However, the adverse effects of this treatment are common and can be life threatening. Benefits and risks for each individual patient will have to be weighed carefully in treatment-decision discussions.

Programmed death-1 inhibitors help people with advanced lung cancer live longer.

Lung cancer is the most common cancer worldwide, with 1.8 million new diagnoses in 2012. It is also the leading cause of cancer-related death, taking a staggering 1.6 million lives each year. This is equivalent to three people dying every minute.7

Non–small-cell lung cancer (NSCLC) accounts for the great majority (85%) of all lung cancers. People with advanced NSCLC have a grim prognosis. Until the approval of the programmed death-1 (PD-1) checkpoint inhibitors pembrolizumab and nivolumab in 2015, the median life expectancy with standard chemotherapy was only 10 months.

In 2016, researchers reported findings from a large trial comparing pembrolizumab with standard docetaxel chemotherapy in patients with previously treated, advanced, programmed death ligand-1 (PD-L1) –positive NSCLC.8 Among all patients treated in the study, the median survival was 10.4 months with pembrolizumab versus 8.5 months with docetaxel. In the group of patients with higher levels of PD-L1 (at least 50% of cells positive for PD-L1), the median survival with pembrolizumab was even longer (14.9 v 8.2 months). In addition, the rate of severe adverse effects was much lower with pembrolizumab than with docetaxel (16% v 35%). Not only does immunotherapy offer patients with NSCLC the chance to live longer, it is also far easier to tolerate than chemotherapy for many patients.

These findings established pembrolizumab as a new standard option for patients with previously treated, advanced NSCLC. The study also sparked a national conversation about the importance of PD-L1 biomarker testing to select patients who are most likely to benefit from immune checkpoint inhibitors.

Meanwhile, findings from a large clinical trial suggest that pembrolizumab may be more effective than chemotherapy as an initial treatment for patients who have metastatic NSCLC with high levels of PD-L1 (> 50% of cancer cells are PD-1 positive),9 whereas a similar study failed to demonstrate superiority of nivolumab to chemotherapy in this setting.10

These findings will change initial treatment of metastatic NSCLC in that every newly diagnosed patient will need to be tested for PD-L1. Patients with high PD-L1 levels will likely receive immuno-therapy rather than chemotherapy.

Another immune checkpoint inhibitor, atezolizumab, was approved by the FDA in 2016 for patients with previously treated, metastatic NSCLC.11 The approval was based on two large clinical trials, which showed that patients who received atezolizumab lived longer (13.8 and 12.6 months, respectively) than those who received standard docetaxel chemotherapy (9.6 and 9.7 months, respectively). The most common adverse effects related to treatment with atezolizumab included fatigue, decreased appetite, shortness of breath, cough, and nausea. Atezolizumab is a PD-L1 inhibitor previously approved for treatment of bladder cancer.

In October 2016, the FDA approved pembrolizumab for use as first-line treatment for patients with advanced, PD-L1–positive NSCLC.12 A breakthrough therapy designation had previously been granted for the same use. These studies collectively mean that the historical standard treatment of advanced lung cancer (i.e., chemotherapy) has finally been displaced by immunotherapy as either first- or second-line treatment.

Voices of Cancer Research: Rebecca Hill

"I'm in remission—I can't believe it myself."

In 2014, Rebecca found out that the lung cancer that she had been previously diagnosed with had returned and spread to other areas. Her doctors quickly ran out of treatment options and suggested hospice. It was then that Rebecca learned about a clinical trial investigating a type of immunotherapy called nivolumab for advanced lung cancer. After one month on the trial, her tumor began to shrink, and the severe pain Rebecca had felt for the last year finally began to subside. Today, the cancer is in remission.

Rebecca is an active participant in the #LCSM Twitter community and is pictured with her oncologist Katherine Wang, MD, PhD.

First new treatment for bladder cancer in three decades.

An estimated 76,960 people were diagnosed with bladder cancer in the United States in 2016, and 430,000 were diagnosed worldwide in 2012.7,13 Bladder cancer is more common among men than women. In fact, bladder cancer is the fourth most common cancer among men.

It is estimated that 16,390 deaths resulting from bladder cancer occurred in the United States in 2016. The most commonly diagnosed type of bladder cancer is superficial bladder cancer (i.e., cancer that has not yet spread outside of the bladder), which can typically be treated successfully. However, people who have advanced bladder cancer are in desperate need of better therapies. Only 15% of patients with bladder cancer that has spread to distant parts of the body live 5 years after diagnosis.14 Cancer.Net provides details about bladder cancer for patients, caregivers, and others seeking reliable information.

There had been little progress in the treatment of advanced bladder cancer for several decades until the FDA approval of the immunotherapy atezolizumab in May 2016.15 Atezolizumab was also the first PD-L1 checkpoint inhibitor to gain FDA approval for any use.

The approval of atezolizumab was based on an early clinical trial of patients with previously treated metastatic urothelial cancer, the most common type of bladder cancer.16 Among patients with bladder cancer that worsens after initial cisplatin- or platinum-based chemotherapy, historical response rates to chemotherapy have been poor, with tumors shrinking in only approximately 10% of patients. In contrast, the response rate to atezolizumab was 15% among all patients in the study and 27% in the group of patients with more PD-L1–positive immune cells.

Immunotherapy has played an important role in the treatment of early bladder cancer since 1990, with the FDA approval of Bacillus Calmette-Guérin (BCG), a live bacterium related to cow tuberculosis. BCG has been used as a vaccine to prevent tuberculosis for more than a century. It is not fully understood how BCG works against bladder cancer, but many researchers think that it triggers the immune system to destroy cancer cells. The approval of atezolizumab has paved the way for further investigation of checkpoint inhibitors in bladder cancer, including a late-stage trial comparing atezolizumab with standard chemotherapy in patients with bladder cancer that worsened after platinum-based chemotherapy (ClinicalTrials.gov identifier: NCT02302807).

In 2016, researchers also reported promising early findings from two clinical trials of pembrolizumab in patients with advanced bladder cancer. In a late-stage clinical trial, patients with previously treated cancer who received pembrolizumab lived longer than those who received chemotherapy.17 Another clinical trial suggested that pembrolizumab may also be effective as an initial (first-line) treatment for patients with advanced bladder cancer who are not eligible for cisplatin chemotherapy. Tumors shrunk in 24% of all patients treated in the study. In the group of patients with high levels of PD-L1 in tumor and immune cells, 37% experienced tumor shrinkage, and 13% experienced a complete response.18 Pembrolizumab is also being tested in patients with earlier-stage, superficial bladder cancers that are resistant to BCG (ClinicalTrials.gov identifiers: NCT02808143 and NCT02625961). Meanwhile, another early study is exploring a different PD-L1 checkpoint inhibitor, avelumab, as a maintenance therapy for patients with bladder cancer that did not worsen after initial chemotherapy (ClinicalTrials.gov identifier: NCT02603432).

Voices of Cancer Research: Susan Corcoran

Susan Corcoran
"This clinical trial saved my life."

When Susan’s bladder cancer returned in 2013, doctors told her the cancer had spread, and treatment would only slow its growth temporarily. Now, nearly four years later, Susan is cancer-free, thanks to a clinical trial of an immunotherapy called atezolizumab.

Susan has been on the trial for more than two years now, receiving an infusion of atezolizumab once every three weeks. She has spent this time traveling with her husband, dragon boating with fellow cancer survivors, and visiting her grandchildren.

Susan is a member of the Bladder Cancer Advocacy Network (BCAN).


Immunotherapy extends life after head and neck cancer recurrence.

More than 600,000 people around the world are diagnosed with head and neck cancer every year, with nearly 50,000 in the United States alone.19,20 This type of cancer is difficult to treat, particularly if it recurs or spreads (i.e., metastasizes). Patients with squamous cell head and neck cancer that worsens within 6 months of treatment with chemotherapy have no life-extending  therapy options.

However, a recent clinical trial suggests that nivolumab may offer such patients a chance to live longer.21 The estimated 1-year survival rate was more than two-fold higher among patients treated with nivolumab than that among those treated with standard chemotherapy (36% v 17%). The median survival was 7.5 months in the nivolumab group and 5.1 months in the chemotherapy group.

Fewer patients in the nivolumab group (13% v 35%) had severe treatment-related adverse effects. In addition, quality of life remained stable among patients who received nivolumab but deteriorated among those who received chemotherapy. Based on the results of this trial, the FDA approved nivolumab for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck in November 2016.22

Ongoing clinical trials are exploring whether combining nivolumab with ipilimumab may further improve patient outcomes (ClinicalTrials.gov identifiers: NCT02741570 and NCT02823574). Meanwhile, pembrolizumab is already approved as treatment for patients with recurrent or metastatic head and neck cancer.

Chance to slow ovarian cancer progression.

Compared with other cancers, ovarian cancer is relatively uncommon, with an estimated 22,280 new diagnoses in the United States in 2016.23 Worldwide, 239,000 women were diagnosed with ovarian cancer in 2012.7

Nonetheless, ovarian cancer is the fifth most common cause of cancer-related death among US women, causing an estimated 14,240 deaths in 2016.23 Because of the lack of specific symptoms, ovarian cancer has often reached an advanced stage by the time of diagnosis. Despite surgery and chemotherapy, more than 70% of women with ovarian cancer that goes into remission eventually experience a relapse. Fewer than half of such women live 5 years after diagnosis.

Early research published in 2015 suggests that nivolumab may help some women with ovarian cancer that has relapsed after platinum-based chemotherapy. In an early clinical trial of 20 women, three (15%) experienced tumor shrinkage after treatment with nivolumab, and an additional six (30%) had stable disease (i.e., tumors neither shrinking nor growing).24 Two women experienced complete remission, one of whom had a type of ovarian cancer particularly resistant to chemotherapy (clear cell carcinoma).

These early findings have spurred further research on how best to incorporate immunotherapy into the treatment of ovarian cancer. Several ongoing clinical trials are exploring nivolumab in combination with other immunotherapies for women with recurrent ovarian cancer (ClinicalTrials.gov identifiers: NCT02737787, NCT02335918, and NCT01928394).

Hodgkin lymphoma seems particularly susceptible to PD-1 inhibitors.

Hodgkin lymphoma is a cancer of the lymphatic system. It is a fairly uncommon cancer, with an estimated 8,500 people diagnosed in the United States in 2016.25 Hodgkin lymphoma is more common among young adults and men than it is among women.

Classic Hodgkin lymphoma is the most common type of Hodgkin lymphoma, accounting for 95% of all cases. The survival rate for classic Hodgkin lymphoma has been increasing for the past 40 years as a result of treatment improvements. Most patients with classic Hodgkin lymphoma achieve good outcomes with initial chemotherapy, and 86% will live 5 years after diagnosis.

However, in approximately 20% to 30% of patients, classic Hodgkin lymphoma will relapse after initial treatment or will not respond to therapy at all. Such patients require further, more intensive treatment, such as high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT). If the cancer relapses after ASCT, a newer regimen combining a targeted drug with chemotherapy, brentuximab vedotin, can extend survival, but in many patients, the lymphoma eventually worsens despite treatment.

Research reported in 2016 led to a new treatment option for such patients: nivolumab.26 This advance stems from an earlier discovery of genetic changes in malignant classic Hodgkin lymphoma cells called Reed-Sternberg cells. The genetic changes result in an abundance of immune checkpoint molecules PD-L1 and PD-L2, which help the cancer cells dampen immune responses through the PD-1/PD-L1 checkpoint. This insight suggests that classic Hodgkin lymphoma may be particularly susceptible to PD-1 and PD-L1 immune checkpoint inhibitors.

A recent analysis of biopsy samples from newly diagnosed patients with classic Hodgkin lymphoma showed that the genetic changes that lead to an abundance of PD-L1 and PD-L2 markers (polysomy, copy gain, and amplification) are extremely common.27 Such genetic changes were found in 97% of the 108 specimens tested. This genetic underpinning maybe the reason the response rates to PD-1 inhibitors are higher in classic Hodgkin lymphoma than in any other type of cancer studied to date.

The FDA approval of nivolumab for classic Hodgkin lymphoma was based on an early clinical trial in which lymphoma went into remission in 53 (66%) of 80 patients and disappeared entirely in seven.28 Nearly all patients with classic Hodgkin lymphoma who responded to the treatment had at least a 50% reduction in the amount of cancer in the body, and responses lasted 8 months, on average. Nivolumab was generally well tolerated. The most common adverse effects of any grade were fatigue, infusion-related reaction, and skin rash. Severe adverse effects, such as low blood counts (neutropenia) and liver enzyme abnormalities (increased lipase), occurred in only 5% of patients.

In another early trial, pembrolizumab was also effective among young patients with relapsed or treatment-resistant classic Hodgkin lymphoma.29 In 20 (64%) of 31 patients, the cancer went into remission, and of those patients, five experienced complete remission. Nearly all patients had some reduction in tumor size, and most responses lasted more than 24 weeks. In April 2016, the FDA granted pembrolizumab breakthrough therapy designation for treatment of relapsed classic Hodgkin lymphoma.

Further research into PD-1 checkpoint inhibitors as therapy for relapsed as well as newly diagnosed classic Hodgkin lymphoma is underway. Ongoing clinical trials are exploring combinations of nivolumab with brentuximab vedotin and ipilimumab (ClinicalTrials.gov identifiers: NCT02758717, NCT01896999, and NCT02304458). Pembrolizumab is also being tested in a range of other hematologic malignancies, as well as in multiple myeloma (ClinicalTrial.gov identifier: NCT01953692).

Emerging Clues on Patient Selection

Despite the broadening landscape of immunotherapy use, a difficult biology puzzle remains to be solved. Why do immune checkpoint inhibitors work so well in some cancers and not at all in others? Among patients with the same type of cancer, why do some respond to immunotherapy while others do not?

The next chapter of immunotherapy research will focus on answering these questions. Given the high cost and considerable adverse effects of immunotherapy approaches, it is all the more important to be able to determine who is likely to benefit the most. Although there can never be complete certainty about whether a cancer will respond to treatment, in most cases physicians can at least estimate the likelihood of benefit, based on the biologic characteristics or biomarkers of the patient and the tumor.

Scientists are only beginning to unravel the biomarkers that may predict a favorable response to immunotherapy. For example, researchers expected that cancers with high levels of PD-L1 would respond well to PD-1 checkpoint inhibitors and that those without PD-L1 would not benefit at all. However, in a number of different cancers, such as ovarian cancer and melanoma, the relationship between PD-L1 and response to PD-1 checkpoint inhibitors has been less clear. In several clinical trials, cancers with even low levels of PD-L1, including some lung cancers, responded to PD-1 inhibitors.

A major issue is the lack of standardization of PD-1 and PD-L1 analyses. It is unclear which assay or reagent is optimal or whether expression in only the cancer cells or in cancer cells plus surrounding stromal and/or immune cells should be counted. Furthermore, even using one assay and one method of analysis, cutoffs have varied. These issues need to be resolved before this marker can be considered sufficiently robust for clinical decisions.

Meanwhile, researchers are also exploring what causes cancers that shrink in response to PD-1 checkpoint inhibitors to eventually start growing again. A pilot study of patients with melanoma suggested that mutations in certain immune-related genes may be responsible for development of resistance to PD-1 blockade (this study was supported in part by a grant from the NIH).30

FDA Breakthrough Designation and Priority Review

molecule map graphicThe FDA breakthrough therapy designation serves to expedite the development and review of drugs for treating serious or life-threatening illnesses where preliminary clinical data suggest a drug may provide a substantial improvement in patient outcomes. The designation helps ensure patients gain faster access to promising new treatments through FDA approval. A priority review designation means the FDA aims to take action on an application within 6 months.

Checkpoint Inhibitors Work Well Against Hypermutated Cancers

Although research on biomarkers for immune checkpoint inhibitors and other types of immunotherapy is still evolving, a few key clues have emerged. For one, it seems that tumors with a large number of mutations are more susceptible to checkpoint inhibitors. The likely explanation for this is that tumors with more mutations make more abnormal proteins (antigens) that the immune system recognizes as foreign.

Several tests have been proposed to evaluate mutational burden. One involves sequencing the entire genome of the cancer and simply counting the number of mutations. Yet another approach is to sequence only a selected panel of representative genes and again determine the rate of mutations within the panel. A third is to evaluate surrogate markers of mutational frequency. Another assay determines the presence of a hypermutatable phenotype, such as apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) enzymes.

Cancers with a large number of mutations, so-called hypermutated cancers, are primarily those caused by tobacco (e.g., lung, head and neck, and bladder cancers) or UV light exposure (e.g., melanoma and head and neck cancer). In fact, tobacco and UV light exposure have been linked to unique patterns of genetic changes or genetic signatures.31 It is therefore not surprising that in clinical trials to date, those are the cancers in  which immune checkpoint inhibition has been the most effective.

Scientists have also reported that cancers of patients who have a genetic abnormality called mismatch repair (MMR) deficiency, which undermines the ability of a cell to repair DNA damage, also have many mutations. Early research suggests that patients with MMR-deficient colorectal or brain cancer benefit from checkpoint inhibitors. These treatments, however, have low efficacy in patients with the same cancers that are not MMR deficient.

Taken in total, these exciting data are promising but preliminary. It is hoped that ongoing studies will help to determine if one or more tests can be used to focus immune checkpoint inhibitor therapy on those patients most likely to benefit.

Colorectal cancer.

MMR deficiency occurs in 15% of colorectal cancers, but it may also occur in other gastrointestinal cancers, as well as in endometrial, prostate, and ovarian cancers. A clinical trial reported in 2015 points to a relationship between MMR deficiency and response to immune checkpoint inhibitors (this study was funded in part by a grant from the NIH).32 Among patients with MMR-deficient colorectal cancers, four of 10 responded to the PD-1 checkpoint inhibitor pembrolizumab. In contrast, none of the 18 patients without MMR deficiency responded to pembrolizumab. Patients with MMR deficiency had a mean of 1,782 mutations per tumor, whereas those with normal MMR function had only 73 mutations per tumor.

Although more research is needed, these early findings suggest that testing for MMR deficiency or the number of mutations in the tumor, so-called mutational load, may help identify patients who are likely to benefit from PD-1/PD-L1–directed immunotherapy. Such tests are already available in the clinic.

Childhood brain cancer.

In 2016, researchers reported that another MMR-deficient cancer may be susceptible to checkpoint inhibitors: pediatric glioblastoma multiforme (GBM).33 This is a hard-to-treat cancer. Most children with GBM will experience a recurrence of cancer despite surgery, radiation therapy, and chemotherapy. With a median survival of 6 months, children with recurrent GBM are in urgent need of effective therapies.

The study focused on children with a rare childhood cancer predisposition syndrome known as biallelic MMR deficiency. All children with this syndrome develop cancer in the first two decades of life, most commonly brain, blood, or GI cancer.

The researchers analyzed the rates of genetic mutations in 37 biallelic MMR-deficient tumors from different tissues. Although all high-grade tumors had large numbers of mutations (1,589 on average), biallelic MMR-deficient GBMs had the highest by far (17,740 mutations on average), and biallelic MMR-deficient GBMs had significantly more mutations than all other pediatric or adult brain cancers.

Given previous research suggesting that tumors with a large number of mutations respond well to immune checkpoint inhibitors, researchers expected to see good results in pediatric biallelic MMR-deficient GBM. In this pilot study, two siblings with recurrent biallelic MMR-deficiency were treated with nivolumab. After 12 weeks of therapy with nivolumab, tumors shrank in both children, and their health condition improved. After 9 and 5 months of therapy, respectively, the sister and brother had resumed schooling and daily activities.

According to the authors, this is the first report of durable responses to immune checkpoint inhibitors for recurrent GBM. These findings are encouraging, because most children with recurrent GBM experience disease worsening within only 1 or 2 months from time of recurrence and die within 3 to 6 months.

The findings may also have implications for adult patients with GBM, as well as in other cancers with MMR deficiency. More broadly, this research underscores the possible utility of genetic testing to select patients for immune checkpoint inhibitor therapy.

Merkel cell carcinoma. 

Another rare cancer that seems to be susceptible to PD-1 checkpoint inhibitors is an aggressive skin cancer called Merkel cell carcinoma. Advanced Merkel cell carcinoma typically worsens within 3 months of initial treatment with chemotherapy.

As with other skin cancers, Merkel cell carcinoma is caused by exposure to UV light. In addition, approximately four of five occurrences of Merkel cell carcinoma are linked to infection with the Merkel cell polyomavirus (MCPyV).

PD-L1 is found in half of Merkel cell carcinomas, and PD-1 is present on both the cancer-specific and the MCPyV-specific immune cells. Furthermore, the median number of mutations in MCPyV-negative Merkel cell carcinoma (i.e., 1,121) is greater than that reported for other cancers that respond to PD-1/PD-L1 checkpoint inhibitor therapy. This high number of mutations, coupled with PD-1 and PD-L1 markers, suggests that Merkel cell carcinoma may be well suited for treatment with a PD-1 checkpoint inhibitor.

In a pilot study, tumors shrank in 14 (56%) of 26 patients with advanced Merkel cell carcinoma on treatment with pembrolizumab (this study was funded in part by a grant from the NCI).34  The treatment responses lasted from 2.2 to 9.7 months. In another clinical trial, 28 (32%) of 88 patients with chemotherapy-resistant Merkel cell carcinoma experienced tumor shrinkage after treatment with the PD-L1 inhibitor avelumab.35 Although longer follow-up and larger studies are needed, these early findings suggest that checkpoint inhibitors may slow the growth of Merkel cell carcinoma.

Merkel cell carcinomas associated with MCPyV have 100 times fewer mutations (median, 12 mutations) than MCPyV-negative cancers. In fact, MCPyV-positive tumors have fewer mutations than reported for cancers that respond poorly to PD-1 inhibitors, such as prostate and pancreatic cancers. Despite this small number of mutations, MCPyV-positive tumors have higher response rates to pembrolizumab (62%) than MCPyV-negative tumors (44%).

Researchers postulate that MCPyV-positive tumors may respond well to immunotherapy because viral proteins (antigens) trigger an immune response. This means that when PD-1 checkpoint inhibitors unleash the immune system, it is already primed to react against the cancer. This finding may have implications for treatment of other cancers linked to viruses.

For additional notable advances in cancer immunotherapy, please see Appendix Table A1.

View References.


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