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Medical News & Perspectives
January 15, 2019

Immunotherapy 2.0: Improving the Response to Checkpoint Inhibitors

JAMA. 2019;321(2):131-133. doi:10.1001/jama.2018.18306

In 2013, Science named cancer immunotherapy its Breakthrough of the Year, and in 2018, the Nobel Prize in Physiology or Medicine was awarded to the 2 researchers who helped established this paradigm-shifting approach to cancer treatment.

James Allison, PhD, of MD Anderson Cancer Center and Tasuku Honjo, PhD, of Kyoto University, Japan, shared the prize for elucidating 2 different immune checkpoint pathways that put the brakes on CD8+ T cells, dampening their killer instincts and preventing them from destroying cancerous cells.

In the mid-1990s, Allison showed that blocking the cytotoxic T-lymphocyte protein 4 (CTLA-4) protein could shrink tumors in mice. Around the same time, Honjo discovered a second set of brakes, the programmed cell death protein (PD-1) pathway. These immune checkpoint pathways originally evolved to prevent T cells from attacking healthy tissue, but tumors can exploit this strategy to “turn off” T cells that otherwise might zero in on cancer cells.

This work led to the development of immune checkpoint inhibitors including the anti-PD-1 monoclonal antibodies pembrolizumab and nivolumab. Both bind to PD-1 and prevent it from binding to its companion protein, programmed cell death ligand (PD-L1), on the target cancer cell, thereby exposing the cancer cell to immune attack. Other checkpoint inhibitors, such as atezolizumab, achieve the same effect by targeting PD-L1 on the cancer cell. Antibodies to CTLA-4 that include ipilimumab work in complementary fashion to anti–PD-1/PD-L1 agents. These immune checkpoint inhibitors, as well as several others, are now approved by the US Food and Drug Administration (FDA).

Despite their enormous potential, checkpoint inhibitors at present only help some patients with certain types of cancer. These include melanoma, lung cancer, renal cell carcinoma, and bladder cancer, as well as cancers that have microsatellite instability with high mutational load. And even among these tumor types, not all respond to checkpoint inhibitors.

Researchers are working to sort out the fundamental rules of how to best use checkpoint inhibitors to maximize their efficacy, minimize their toxicity, and expand their use across a greater range of cancers.

Biomarkers for Prediction

Close to 2000 clinical trials involving checkpoint inhibitors, alone or in various combinations, are currently under way.

In attempts to enhance the efficacy of immunotherapies, numerous trials are combining checkpoint inhibitors that target both CTLA-4 and PD-1/PD-L1. Although often more effective than monotherapy, combination approaches do carry a greater risk of adverse events. However, reliable biomarkers are needed to guide patient selection for both monotherapy and combination therapy.

Padmanee Sharma, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, has been working to develop and improve checkpoint inhibitors for many years, along with her colleague and husband Allison. As scientific director of MD Anderson’s immunotherapy platform, she is heading up a new clinical biomarker study to evaluate CD8+ T-cell infiltrate in tumors as a biomarker for predicting patient response to checkpoint inhibitors.

The premise of the study is that “hot” tumors with high CD8+ infiltrate will respond to PD-1 inhibitors like nivolumab, whereas “cold” tumors with a low level of CD8+ T cells may need an extra push from a CTLA-4 inhibitor to help drive T cells into the tumor. As such, participants will be assigned to either nivolumab monotherapy or nivolumab and ipilimumab combination therapy depending on whether their tumors have high or low CD8+ T–cell burden, respectively.

Patients with advanced metastatic cancer of all types are being accepted into the trial. Sharma and her colleagues hypothesize that some percentage of all solid tumors—even those considered “cold” like pancreas and prostate cancers—could have a high CD8+ T–cell signature that might render them responsive to checkpoint blockade.

Another biomarker currently being evaluated by the FDA is tumor mutational burden (TMB). Each mutation in a tumor has the possibility of generating a neoantigen, which can act as a red flag to the immune system alerting it to a potential invader, said Matthew Hellmann, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York.

Several years ago, Hellmann and his colleagues showed that patients with non–small cell lung cancer (NSCLC) with a high TMB did well while treated with pembrolizumab. Since then, a positive association between a high TMB and response to checkpoint inhibitors has been found in most cancers investigated, he said.

A prime example of this can be seen in patients with a genetic condition caused by a deficiency in mismatch repair genes, which leads to the development of microsatellite instability–high tumors. In 2017, pembrolizumab received FDA approval for use in microsatellite instability–high tumors, irrespective of the site of origin of the cancer. This was the first time the FDA granted approval based on a biomarker rather than a single tumor indication.

However, no biomarker is perfect. For example, 4 different immunohistochemistry tests to detect high PD-L1 tumor expression have received FDA approval for certain cancer indications, including NSCLC, but PD-L1 expression does not always accurately predict which patients will or will not respond to checkpoint inhibition.

“Considered in the composite, various biomarkers may provide different lenses on patient response,” noted Hellmann.

Gut Check

The diversity and composition of the gut microbiome is another factor that may influence response to checkpoint inhibitors, according to several recent studies from investigators in Houston, Chicago, and France. Researchers are now interested in investigating the use of gut microbes as a biomarker and modulator of checkpoint blockade responses.

Jennifer Wargo, MD, MMSc, at MD Anderson Cancer Center is launching a phase 1 trial, in partnership with the Parker Institute and Seres Therapeutics, Cambridge, Massachusetts, to explore both possibilities. The study will randomize patients with metastatic melanoma to 1 of 3 treatments before initiating anti–PD-1 therapy: an oral pill containing fecal microbiota from anti–PD-1 responders; an oral pill containing a proprietary mix of microbes that mimic key taxa found in anti-PD-1 responders; or placebo.

The researchers will be examining the gut microbiome longitudinally throughout treatment to ensure stability and engraftment of introduced microbiota. Although the study won’t recommend a specific diet to help maintain microbial transplants, it’s something the researchers are considering for future studies.

In a separate phase 2 trial, Hassane Zarour, MD, at the University of Pittsburgh, is looking into whether a fecal microbiota transplant from long-term anti–PD-1 responders could improve PD-1 inhibitor efficacy in patients with PD-1 resistant melanoma.

Similar to Wargo and others, Zarour and his collaborators at the National Cancer Institute (NCI) are aiming to determine which specific microbiota regulate the response to checkpoint blockade. Wargo pointed out that there’s still a great deal of work to be done before they will have zeroed in on “the optimal consortia of bacteria that would be the secret sauce to enhance response to checkpoint blockade,” but these studies are important first steps.

Breaking the Glass Ceiling

A response to checkpoint inhibitors requires that T cells be in the tumor microenvironment. If they aren’t there already, they somehow need to get there, said James Gulley, MD, PhD, chief of the genitourinary malignancies branch at NCI, Bethesda. Many tumors evade T-cell infiltration, and a variety of approaches are being explored to solve this problem.

One molecular sentinel barring T cells from entering the tumor microenvironment is transforming growth factor β (TGF-β), a cytokine with many functions, including immunosuppression. To overcome this barrier, Gulley has been carrying out studies with the agent M7824, which is a bifunctional fusion protein that combines a monoclonal antibody against PD-L1 with a “trap” that vacuums up TGF-β.

Gulley and his team have started a phase 1 and 2 trial using M7824 in patients with metastatic castration–resistant prostate cancer, a cold tumor in which there isn’t much underlying immune response. The novel trial design expedites the evaluation of 4 different experimental agents aimed at 5 different immunologic targets. “If we studied each of these drugs alone in successive phase 2 studies, it would take too long,” said Gulley.

Enrollment in the 3 study groups will advance sequentially, with each subsequent group adding an immunotherapy agent after the safety of the drug combination administered in the previous group has been demonstrated. All patients will receive M7824.

“It’s an adaptive trial design in which we keep pushing, adding another drug until we get a clear clinical signal,” said Gulley.

This approach is an attempt to hit many immune targets at once “by engaging, expanding, and enabling the immune system to work in the tumor microenvironment,” he explained. “We are trying to quickly see what will break the back of immune resistance in these cancers.”

Another innovative approach is exploring the use of CD40 antibody therapy to prime the immune system and sensitize tumors to checkpoint inhibitors. Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center at Penn Medicine, Philadelphia, said that data from his laboratory and others suggest CD40 acts as a switch to convert cold tumors, which can’t mount a sufficient immune response, to hot ones that can. The CD40 antibody is an agonist that turns on this switch.

Vonderheide is partnering with the Parker Institute on a phase 1b and 2 clinical trial looking at whether an anti-CD40 antibody can improve the efficacy of checkpoint blockade in patients with pancreatic cancer who normally don’t respond to immunotherapy. All patients not previously treated for metastatic disease will also receive standard of care chemotherapy. Patients will be randomized to receive the anti-CD40 antibody, nivolumab, or both the anti-CD40 antibody and nivolumab.

The combination of anti-CD40 antibody with nivolumab is also being tested in a clinical trial involving patients with metastatic melanoma and lung cancer for whom checkpoint blockade hasn’t worked. The hope is that this approach will lead to effective immune therapy even in the most refractory of cancers.

“It’s our way of trying to break the glass ceiling of what checkpoint therapy can achieve,” said Vonderheide.

Earlier and Safer

Researchers are also studying checkpoint inhibitor therapy in earlier stages of disease, the theory being that these tumors may respond better because they have yet to develop a good defense against immune attack.

Suzanne Topalian, MD, of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, pointed out that nivolumab was FDA approved last year for adjuvant treatment of melanoma in patients with lymph node involvement or metastasis after surgical resection.

Topalian and others are also exploring the use of checkpoint inhibitors in the neoadjuvant setting, before surgery rather than after, in a variety of cancers. Her group recently published results from a pilot study that was the first report of using nivolumab preoperatively for patients with untreated, early-stage NSCLC, she said.

Researchers are also working to better understand adverse inflammatory effects of immunotherapy, referred to as immune–related adverse events (irAEs). Any organ can potentially be affected, but the skin, gastrointestinal tract, endocrine glands, and liver are most commonly involved.

According to clinical practice guidelines, most irAEs can be mitigated by dose modification, discontinuation of therapy, or administration of steroids. However, rare and irreversible conditions such as type 1 diabetes can occur. The Parker Institute has been building a strategic plan to try to tackle some of the most perplexing questions surrounding irAEs, said Jeffrey Bluestone, PhD, professor at the University of California, San Francisco, and president and CEO of the Parker Institute.

The goal of this work, said Bluestone, is to learn more about the biological, biochemical, and genetic basis for these adverse events to identify who is most at risk and to devise ways to avoid them. In doing so, “we may also learn more about what causes type 1 diabetes to arise in the absence of these therapies,” he said.

Despite the obstacles that limit the efficacy and safety of checkpoint inhibitors, Bluestone emphasized how these drugs are revolutionizing cancer care. “The bottom line is we aren’t at the beginning of the end, we’re at the end of the beginning,” he said.

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