Determining Why Not All Patients Respond to PD-1 Inhibitors

A Conversation With Robert H. Pierce, MD

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Robert H. Pierce, MD

One of the biggest hurdles facing immunotherapy today is identifying the patients who respond and then finding means to convert nonresponders into responders.

—Robert H. Pierce, MD

Recent research1 conducted by Robert H. Pierce, MD, and his colleagues investigating why PD-1 (programmed cell death protein 1) inhibitors result in remarkably durable clinical remissions in some patients with melanoma, whereas others reap a short-term benefit or no benefit at all is showing that response is likely dependent on the presence of PD-L1 and tumor-infiltrating lymphocytes in the patient’s tumor. Termed “adaptive immune resistance,” this compensatory upregulation of PD-L1—the ligand that “turns off” antigen-specific CD8-positive T cells by activating the PD-1 receptor—may be the potential biomarker researchers have been looking for to accurately predict response to anti–PD-1 therapy.

Dr. Pierce, Chief Scientific Officer at OncoSec Medical, a biopharmaceutical company developing DNA-based intratumoral cancer immunotherapies, is planning on using the information gained from this research to investigate whether combining anti–PD-1 drugs, such as pembrolizumab (Keytruda), with therapies that can drive immunogenicity and increase tumor-infiltrating lymphocytes will lead to enhanced responses not just in melanoma patients, but in patients with other cancer types as well.

In January 2015, OncoSec Medical announced that it is launching a pilot study to assess the effectiveness of its investigational intratumoral immunotherapy ImmunoPulse IL-12 (interleukin 12) to increase tumor-infiltrating lymphocytes in patients with triple-negative breast cancer.

In a wide-ranging interview with The ASCO Post, Dr. Pierce talked about progress being made in immunotherapy; the use of genomic sequencing in the design of clinical trials; and how personalized medicine will increase the cost of cancer care.

Phenomenal Future for Immunotherapy

What role will immunotherapy play over the next decade? Will it be an effective treatment that can be utilized in many different cancers?

Yes, absolutely. I think that is the picture that is clearly emerging. How immunotherapy moves forward will be interesting to observe, because certainly PD-1 inhibitors are proving to be relatively nontoxic and highly effective in at least a significant subpopulation of patients in many different tumor types. However, one of the biggest hurdles facing immunotherapy today is identifying the patients who respond and then finding means to convert nonresponders into responders.

Right now, there is a debate about how to sequence therapy for the greatest effectiveness. For instance, in the future, an oncologist who has a melanoma patient with a BRAF mutation and a great burden of disease may want to treat him first with a BRAF inhibitor to debulk the cancer and then with a PD-1 inhibitor.

Conversely, there may be other circumstances in which you might want to invert that treatment sequence, so I see a future with a lot of choices for potential combinations that are coming down the pike. There is a phenomenal future for immunotherapy both in terms of combining multiple immunotherapies together and also putting immunotherapies together with targeted agents and chemotherapies.

Over time, given its relatively benign safety profile, we will likely see PD-1 therapeutics being given in earlier lines of treatment to those patients whose tumors are characterized by a “responsive phenotype.”

Next-Generation Sequencing and Drug Development

Advances in genomic sequencing are turning every cancer into essentially a rare disease. How will this change the way pharmaceutical companies develop and test drugs for individual patients?

Next-generation DNA and RNA sequencing technologies are allowing us to carve out smaller and smaller buckets of cancer types. I’m a pathologist by training, and we tend to think of tumor types by virtue of their cell of origin and where the malignant cells arise in the body. What we are seeing with immunotherapies is that the tumor histotype does not seem to matter as much as the immunophenotype. Right now, there are many ways one can imagine that next-generation sequencing can guide drug development.

In immunotherapy, the mutational load in a patient’s tumor may prove to be a critical determinant in response to immune-based therapies—as those mutated peptides are what the immune system recognizes in the tumor as “foreign.” I think we will see a day in the not too distant future where we can determine from next-generation sequencing data that a patient’s tumor has sufficient mutational load to drive an immune response but not enough expression of antigen-processing and presentation machinery and positive co-stimulatory molecules to convert those “virtual” antigens into a bona fide antitumor T- cell response.

In such a patient, perhaps an upfront combination with a proimmunogenic stimulus like intratumoral IL-12 will be considered. Given the power of these evolving technologies, we could speculate all day on the possibilities.

Future Design of Clinical Trials

How will pharmaceutical companies design clinical studies in the future? Will they be modeled more on the “basket” trial approach, in which patients with different cancers but the same specific genetic alteration or mutation are enrolled into a trial investigating a molecularly targeted therapy?

I think there are times when the basket trial approach is appropriate and times when it is not. In particular, response assessments are often very different, according to the tumor type, and then you end up having what amounts to a bunch of different clinical trials bundled together; so in the end, this approach may not add efficiency.

Also, there may be logistic issues stemming from the fact that patients with different tumor types may be seen by different sets of doctors and even different institutions. Despite those limitations, we often look to see whether there is the possibility for a given therapeutic strategy to take advantage of the unifying biology with a basket approach. However, I haven’t been involved in one yet.

Appropriate Use of Biomarkers

Doesn’t the basket-trial approach have the potential to eliminate a lot of waste in the development of new drugs, because the results would signal early on which targeted agents might be most effective for specific mutations?

Yes, that is absolutely true, and I think that model will be very valuable in the future, particularly for drugs targeting oncogenic “driver” mutations. Patient selection in immunotherapy may not prove to be as straightforward. Whether one is testing an immunotherapy or a mutant kinase, the power of the trial lies in how good your patient-selection biomarker is. A truly selective biomarker, such as in detection of mutant BRAF, can enable investigators to see the efficacy of the drug in a smaller and less expensive study.

However, as has often been the case, in the initial development of anti–PD-1 monoclonal antibodies, we knew that we had an effective therapeutic before we had the confidence that we had a good biomarker. And, given that some patients who score “negative” for the various assays still respond to PD-1 blockade, there is some controversy about how to use these biomarkers for patient selection in practice.

I think we simply need to be clear that every assay has a false-negative rate and a false-positive rate and that we must differentiate the use of a biomarker as a drug development tool for enriching the responder population in a clinical trial from that of using a biomarker in clinical practice to determine patient access to—or reimbursement for—a potentially efficacious therapy.

With the appropriate use of response-enriching biomarkers in clinical trials, we hope to accelerate drug approval and get these therapies to patients as soon as possible.

Cost of Drug Development

How will the success of immunotherapy and the development of patient selection biomarkers impact the cost of cancer care?

As we develop effective therapies and those therapies prove to be even more effective in combination and these successes result in even more lines of therapy, it is difficult not to imagine the cost of care going up. So, success is driving some of these costs, but, clearly, this is a good problem to have.

The rising cost of care is a fact that, as a society, we have to wrap our heads around. Although as a “techno-optimist” I like to think that some low-cost, super-effective technology is waiting around the corner, this may be a dangerous fantasy if it keeps us from dealing with the current economic realities.

Effective personalized medicine involves the search for validation and ultimately commercialization of biomarker test kits to classify patients into subpopulations, and this, too, is adding to the cost of drug development. This added dimension of care is something we often do not talk about, but the potential need for codeveloping a companion diagnostic, depending, of course, on the clinical scenario, can present a major economic challenge for smaller companies endeavoring to develop oncology drugs.

The development of adoptive T-cell transfer and chimeric antigen receptor T-cell therapy, which are cost-intensive at the point of care, has been fueling considerable discussion on the rising cost problem. And although these therapies appear to show great promise, many of us have questions about their scalability, commercialization, and, ultimately, how to factor them into the finite cost-of-care universe, which is our reality.

Exploring Biologic Combinations

What major advances in cancer care do you see happening over the next decade? Will there be more cures and conversions of cancer into a chronic disease?

I think the next decade will be characterized by both new cures for some cancers and the conversion of others into controlled chronic states, which are still associated with improved quality of life for patients. In terms of therapeutics, I think the next 10 years will be about exploring biologic combinations—combinations of immunotherapies, combinations of immunotherapy with so-called immunogenic chemotherapy, and combinations of immunotherapy with targeted molecules.

The next stage will be about employing these combinations and harnessing multiple physiologic and cytotoxic mechanisms to attack tumors. Immunotherapy is exciting because of the impressive durability of responses and the characteristic long tail on the overall survival curves. We are all focused on raising the percentage of patients who experience those long-duration responses and significantly increased survival rates.

I recently attended a meeting in which there was fairly sober speculation that combination immunotherapies in melanoma would, in the near future, push that overall survival “tail” north of 50%. Part of this push will be the development of new therapies that enhance immunogenicity, increase tumor-infiltrating lymphocytes, and convert PD-1 nonresponders into responders.

In triple-negative breast cancer, the presence of CD8 tumor-infiltrating lymphocytes not only correlates with response to PD-1/PD-L1 therapeutics, but to response to certain chemotherapeutic regimens as well. In breast cancer, as well as other solid tumor types, I think we are going to find that maximally effective therapy involves a rational combination of immunogenic chemotherapies with immunotherapy, which is really exciting.

One of the emerging areas that I predict will become “hot” is the development of intratumoral cancer immunotherapies, in which we “take the fight to the tumor,” deploying immunostimulatory molecules directly into the tumor to combat the local immunosuppressive microenvironment to drive a systemic antitumor response. I think we are beginning to see this approach as a real opportunity in the treatment of solid tumors such as triple-negative breast cancer. ■

Disclosure: Dr. Pierce is Chief Scientific Officer at OncoSec Medical, a biopharmaceutical company. 


1. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014.