Evidence-Based Oncology
February 2016
Volume 22
Issue SP2

Immuno-Oncology 2016 and Beyond: The Opportunities, Challenges, and Risks

The translation of immuno-oncology agents from the research to the practice arena may provide significant clinical benefit to patients with difficult-to-treat malignancies. The further development and marketing of these agents could escalate the discussion on care equity in a time of constrained resources.

In the late 18th century, a young surgeon at Memorial Hospital, Dr William Cooley, learned of a patient with locally recurrent sarcoma of the head and neck that developed a raging local erysipelas infection caused by Streptococcal pyogenes arising in the necrotic tumor. According to the report, with each wave of fever, the tumor shrank and ultimately disappeared. Cooley searched the boroughs of New York and found the patient alive and well 7 years after his infection, with a large tumor-free scar on his face. Subsequently, Cooley developed various concoctions of bacteria and intentionally infected scores of patients with these toxins, which caused numerous untoward events and even deaths in patients. Curiously, his treatments also led to a collection of dramatic responses and, in some cases, cures.1

Fast forward to experiences with high-dose interleukin 2 (IL-2) and interferons for the treatment of individuals with renal cell carcinoma and melanoma.2 Although the clinical use of high-dose cytokines has led to important clinical insights and, in the case of high dose IL-2, a modest niche in the management of young individuals with cancer, it is reasonable to state that they have not changed the landscape of cancer therapeutics in a material way. Instead, they provide tantalizing clues that, if the immune system could be primed, expanded, and directed to the target (ie, the tumor), the patient might benefit. Their use also highlighted a few simple yet profound questions that required further research: namely, why don’t tumors more readily activate the immune system? Or, if they do lead to immune activation, how do these tumors escape destruction by the immune system?

Several recent developments in immuno-oncology (I-O) offer great opportunities and challenges for all stakeholders in the war on cancer. These include:

  • The approval of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)—binding antibody (ipilimumab)
  • The recent approval of 2 programmed cell death protein 1 (PD-1)—targeted antibodies (nivolumab and pembrolizumab) and the rapid development of other PD-1 and programmed cell death protein 1 ligand (PD-L1)–targeted agents
  • Interesting results with genetically engineered chimeric antigen receptor T cells (CAR-T cells)

These agents, along with a very long list of vaccines, antibodies, and small molecules that trigger immune cell activation, elimination of regulatory cells, or signals that extinguish the immune response, are likely to dominate therapeutic advances in oncology for the next 10 years.

Whereas results supporting the role of the immune system in treating cancer are actually a rediscovery of the work of Cooley, the profound impact of the most recent work is the likelihood that these agents, either alone or in combination (more likely), will democratize the delivery of effective immunotherapy for potentially millions of individuals worldwide in short order—something that neither Cooley nor those who developed high-dose cytokine therapy achieved. This democratization of therapy, with its potential for fantastic benefits in a subset of patients, will raise significant challenges for the healthcare community.

Immunology 101 and Cancer

Life in our natural environment is not possible without a well-functioning immune system. The body is marvelously designed to recognize things that are foreign and then amplify a specific set of immune cells in concert with a variety of other inflammatory aide de camps to assist in the elimination of the invading bacteria, yeast, or viruses. Several sophisticated mechanisms exist to extinguish this immune response when the invading beast is eradicated, as ongoing inflammation and immune amplification are neither energy-efficient nor safe. Individuals born with or acquiring immune defects are prone to infection. Those with deregulated immune systems suffer the ravages of their own immune system directed against their normal tissues and joints with attendant disability.

Cancer arises from the accumulation of at least one, and typically multiple, mutations, which then translate into changes in the structure of key proteins, thus changing the function and the biology of the affected cell and converting the protein into a foreign protein, much like a virus carries proteins on its surface that are recognized as foreign. These mutations provide the cell with a growth advantage, as well as an ability to escape the bounds of its normal anatomical home.3 So why don’t these mutated tumors, which are now at least partially foreign, attract attention and ultimate destruction by the immune system?

A wealth of studies, well outside of the scope of this review, have demonstrated 3 interesting observations.3,4

  • Some tumors effectively shield themselves from the immune system through a variety of mechanisms and can be considered camouflaged.
  • Some tumors do activate the immune cells, but have developed mechanisms to exclude these cells from entering their tumor nests, with the malignant cells essentially residing and expanding in an immune-free fortress.
  • Some tumors express cell surface molecules that deactivate immune cells that have managed their way into the “fortress,” essentially defusing what had been an activated cell poised to eliminate the tumor cell.

Two of the key interactions that defuse the active immune cell are CTLA-4 and PD-L1, found on tumor cells and other inhibitory cells in the tumor microenvironment (the fortress). The CTLA-4 inhibitor, ipilimumab, has demonstrated remarkable activity in a subset of melanoma patients, leading to responses that often take a few months to appear, presumably due to the time it takes to reawaken the immune response to melanoma cells. A second and similar approach is accomplished by antibodies that interrupt the linkage of the PD-1 molecule on the immune cell (the off switch) to the PD-L1 protein on the tumor cell, interrupting the trigger that defuses and thereby extinguishes the immune response.

CTLA-4, PD-1, and PD-L1 are not the only key proteins that modulate the immune system, however. Cells in the tumor microenvironment carry a host of other regulatory molecules that might augment the effectiveness of PD-1. Not surprisingly, pharmaceutical and biotechnology companies are working hard to evaluate whether these targets and agents that bind these targets might enhance the effectiveness of PD-1 agents or prove effective in those patients for whom the PD-1/CTLA-4 agents are not effective.

Although a bit earlier in development, CAR-T cells (genetically modified T cells created and partially expanded in a test tube) can be engineered toward a specific molecule restricted to a specific cancer cell—type of interest.5 One of the major advancements of this field, compared with earlier trials of transferring immune cells (termed “adoptive immunotherapy”) is the ability to expand these cells in the test tube and to provide them with potent activating signals that aid in their expansion and persistence once infused back into the patient. This approach helps to solve 2 of the problems listed above: namely, the ability to develop immune cells against camouflaged tumors and make them resistant to inactivation of exhaustion.

How Effective Are PD-1/PD-L1—Targeted Agents and CAR-T Cells?

The research efforts with CTLA-4 largely focused on persons with advanced melanoma.6 Although clearly an important new drug, ipilimumab impacted only a small portion of those individuals with cancer. The impending democratization of immunotherapy in the last year arises from a number of high-profile clinical trials that have demonstrated activity of PD-1— and PD-L1–binding antibodies in a variety of tumor types, including melanoma; essentially all types of lung cancer, kidney cancer, and bladder cancer; and Hodgkin’s disease.7-13 While the results are most impressive for Hodgkin’s disease,13 with an 87% response rate (most after an unsuccessful bone marrow transplant), immunotherapy’s major impact will likely be in patients with high-risk solid tumors. Studies in melanoma, lung cancer, bladder cancer, and kidney cancer demonstrate that although only 1 in 5 (20%) patients had a reduction in tumor volume, a larger portion have stable disease.7-12 Not yet reported in detail, early anecdotal evidence demonstrates similar activity in a variety of other malignancies, including head and neck cancers; certain types of colon, breast, and ovarian cancer; Merkel cell tumors; and esophageal cancer.

What is most intriguing, however, is not the response rate or the average time to tumor progression, but instead the tail of the curve (Figure). In all the studies looking at these contemporary I-O agents, there is a subset of 10% to 20% of patients who are doing remarkably well more than a year after treatment. Some studies with longer follow-up have demonstrated multi-year responses.6-12 This is distinctly unusual from standard chemotherapy or molecularly targeted agents that inhibit nonimmune targets.

The Tail of the Survival Curve

Patients treated with these I-O agents had widely metastatic and often drug-resistant diseases, with a predicted survival of usually less than a year. In melanoma, where some of the data with ipilimumab is most mature, a subset of patients are 10 years out from therapy, raising the specter that some of these individuals might be cured.6 Although these results are striking, perhaps even more remarkable is that the combination of ipilimumab and nivolumab may provide even more striking long-term survival.7

For patients with advanced cancers that are currently treated with palliative (noncurative) intent, their primary question is, “Can my cancer be cured?” Indeed, other endpoints typically deemed important by oncologists, such as response rates, are low priority in comparison. If these therapies provide multi-year. and perhaps decade-plus remissions, even if that likelihood is low (say 10%), all patients will want a chance at winning on what might be considered a life-saving I-O lottery ticket, compared with the alternative—almost certain death in a year or two with what was until very recently considered best therapy. Interestingly, in a few studies, the toxicity associated with relatively ineffective chemotherapy (the previous standard) was more toxic then the PD-1 inhibitor.10 Thus, PD-1 inhibitors gain a strong foothold based on response, the important “tail of the curve,” and toxicity, and therefore deliver a proverbial “trifecta.”

CAR-T cells involve considerably more time and attention to create and are still being made 1 patient at a time. These therapies will be more challenging to democratize although hundreds of millions of dollars are being invested in automating what for now is a partially manual process.5 The effort has been deemed worthwhile by large pharmaceutical companies and some new biotechnology companies that have garnered huge investments from a variety of stakeholders following dramatic responses in children with acute lymphoblastic leukemia (ALL) and some other leukemias and lymphomas. The broad-scale applicability of CAR-T to leukemia and lymphoma or, more importantly, to solid tumors, is uncertain. One important challenge outside of manufacturing is the significant and, at times, lethal toxicity of this treatment. There can be sizable hospital costs associated with considerable inflammatory responses soon after administration of CAR-T cells. Nevertheless, it is possible that this therapy will provide cures for otherwise incurable conditions, which might support very significant price points with manufacturing. If better strategies are not developed to mitigate clinical costs, the total healthcare cost of this therapy might be very significant.

The Patient and Physician Perspectives

I-O has had a singular impact on patients and providers. Patients have a growing recognition of the potential of I-O agents, including advertisements on national television. Currently, ipilimumab is approved for use in various stages of melanoma, pembrolizumab is approved for use in melanoma and lung cancer, and nivolumab is approved for use in melanoma, lung cancer, and metastatic renal cell carcinoma. With these approvals, patients with a variety of metastatic malignancies are, or soon will be, hearing of interesting results in their tumors. For now, access for these patients is largely through clinical trials, although there is some anecdotal evidence of patients receiving these agents off trial and outside their FDA indications. As these drugs are expensive, the risk of not being reimbursed is real, particularly for physicians in the community who bear the financial risks of unreimbursed drug expenses.

A second challenge for physicians is the management of toxicity. Although hair loss, nausea, and vomiting, all vexing issues associated with chemotherapy, are not issues with I-O drugs, the drugs are far from being free of toxicities. Most notable is that these immune activators can generate unwanted immune or inflammatory responses.7-13 To date, the principal toxicities have been diarrhea (sometimes severe and long lasting), rash, and fatigue. Less common side effects have included dysfunction of the kidneys and liver; more worrisome, a variety of endocrine effects causing abnormalities in the thyroid, pancreas, and pituitary gland that sometimes require long-term hormone replacement. The latter is a new set of toxicities for oncologists who will need to quickly learn to keep these toxicities “top of mind” and become facile at evaluating and managing them. Many of the tissue toxicities, such as colitis, require steroids and occasionally other expensive and toxic agents. Endocrine abnormalities must first be recognized and then managed with hormone replacement therapy, which will require oncologists to either form closer relationships with endocrinologists or take the time to brush up on their endocrinology.

The Pharmaceutical and Biotechnology Perspective

The response by pharmaceutical companies has been dramatic. While Bristol-Myers Squibb and Merck are the early leaders, AstraZeneca, Roche, and others are not far behind. In addition, dozens of pharmaceutical and biotech companies have complementary agents, including vaccines and other small and large molecules. Investments into these ancillary initiatives are moving at full speed. CAR-T cells may either stand alone as a single modality or they might be combined with the above list of novel agents. A quick review of the website reveals well over 100 trials underway in this space, including many large or randomized phase 2 or 3 trials and a large proportion in combination with vaccines and other novel immune-modulatory agents. A small army of medical oncologists is being recruited to pharma to help conduct these trials, and there is a growing concern that the clinical research infrastructure will be strained in an attempt to find the tens of thousands of patients needed to fill the current phase 1 through 3 portfolio of I-O trials.

The Payer Perspective

The implications for those who pay the healthcare bill (insurance companies, employers, and now patients) are likewise daunting. Whereas a course of ipilimumab (4 doses) retails at about $130,000, it’s important to note that the PD-1 inhibitors have an undefined duration of treatment, with some patients on therapy for over a year. A 1-year course of a PD-1 inhibitor is approximately $180,000.14 If early results on the aforementioned cancers pan out, it is possible that 250,000 to 500,000 patients per year might be eligible to receive a course of an I-O agent or agents in the United States.

Of note, studies in melanoma and early results in other tumors suggest that a CTLA-4—binding antibody is likely to work better in combination with a PD-1 inhibitor than either drug alone.7 Indeed, this combination was recently approved by the FDA in melanoma.7 Although a person’s size would determine the total costs associated with treatment with I-O agents, pricing of currently approved drugs, of those expected to be approved soon, and associated healthcare costs will all be very significant. If current drug prices are any indication, it is not hard to imagine that a significant proportion of cancer patients will be prescribed a regimen with a price tag in excess of $200,000 if they remain on therapy for a year. For example, 4 doses of ipilimumab and a year of a PD-1 inhibitor for an 80-kg individual cost $250,000 (note: the dose of nivolumab is lower when combined with ipilimumab). The market size of I-O agents alone in 2022 is predicted by some to be in excess of $30 billion.15 Of note, the total dollars spent on anti-cancer drugs in the United States is currently about $30 billion.

It is important to appreciate that the I-O market is very young, and it is possible that the approval of multiple PD-1 and PD-L1 inhibitors might allow for intra-class price competition, as witnessed with the emerging market of hepatitis C drugs. While first-in-class agents generated a hefty price tag, the entrance of alternative curative therapies led to marked price concessions by manufacturers. The same may happen with I-O agents, largely driven by a consolidating payer landscape.

What Are the Implications for Society?

With FDA approval for lung cancer, melanoma, and renal cell carcinoma, it is reasonable to predict that I-O agents, including additional monoclonal antibodies, CAR-T-cells, and various vaccines or immune-modulatory agents, will be approved in a variety of malignancies. This repertoire could include ALL, Hodgkin’s disease, bladder cancer, head and neck cancer, breast cancer, gastric cancer, Merkel Cell tumors, and specific subtypes of colon16 and endometrial cancers. Furthermore, all potential lethal cancers will be under evaluation by one or more pharmaceutical and/or biotechnology companies. If combinations are advanced, it is likely they will combine multiple novel agents, with the price tag for each agent in excess of $100,000. Whereas a few large pharmaceutical companies might have diverse I-O portfolios that allow them to co-market a drug cocktail at a less astronomical aggregate price, in many circumstances, these agents will come from different companies. The total price tags for these therapies—including monitoring, hospitalizations, and other components of care—could, therefore, easily exceed $200,000 per patient treated.

Assuming the I-O market reaches $30 billion in the next decade, how should we frame this expense? This expense would double the oncology drug spend and increase the oncology total cost by about 20%, but add only a miniscule amount to the multi-trillion dollar healthcare spend. Assuming the full potential of I-O drug cost is realized, will this cost be accretive? The total cost of oncology care was estimated to be $130 billion in 2010, with about one-third of that cost during the last year of a cancer survivor’s life.17 Much of this expenditure is on futile care. Is it possible that these therapies will provide benefits that will reduce hospitalizations and deaths? Can we estimate savings that such therapies might provide to the subset of patients who have long-term benefit? In the absence of such data, it is likely that society will focus on drug price as it grapples with the rising cost of healthcare. We might be in a quandary of having effective drugs, with evidence-based clinical criteria to support appropriate prescribing, at a difficult-to-afford price.

Although ultra-high drug costs have been the norm for rare diseases, the new I-O therapies have the potential to be useful in several hundred thousand patients annually. It is likely something will need to be done to manage this expense. An ideal solution is to identify a biomarker that can distinguish between responders and nonresponders. Early attempts in select tumors may have found a group that has a 40% to 60% chance8,12 of winning the I-O lottery compared with a 10% chance. While this is a start, it is likely that patients with desperate cancer conditions will gladly accept—and perhaps demand—a lottery ticket even if the odds of “winning” are only 10%!

Other possibilities might include variable pricing, for example, dependent on a priori chance of response in a specific tumor, or “indication-based pricing.” Perhaps negotiating early cycles of therapy at deeply discounted prices, with only the full price paid if the therapy is effective (pay-for-performance)? Another option is to consider PD-1 and PD-L1 drugs as a single interchangeable class and having payers, group purchasing organizations, or pharmacy benefit managers limit their formularies for their prescribers based on price. It is conceivable that a multi-tier structure could be developed in which the wealthy can have unfettered access and those less fortunate might have limited access based on age, lottery, or some other yet-to-be-determined system. Even more Draconian strategies include having the government buy a portfolio of I-O agents or companies and provide them to citizens at “cost” (similar to how the CDC provides childhood vaccines to underserved communities). All of the above would require a major legislative overhaul or changes in how we manage the price, prescribing, and delivery of innovative therapies still under patent protection, not to mention a shift of our capitalistic healthcare market to a government service. It is conceivable that if these agents lead to the democratization of a highly effective therapy for a broad swath of the cancer population, the unthinkable may become thinkable.


In summary, it is likely that the translation of I-O from the research to the practice arena may provide significant clinical benefit to patients with difficult-to-treat malignancies, as well as considerable and well-deserved enthusiasm in our efforts to prevail over cancer. The further development and marketing of these agents might also serve as a lightning rod to escalating the discussion of how to equitably deliver important, innovative, and costly medical breakthroughs to a very large population of individuals in a time of constrained resources.

Michael V. Seiden, MD, PhD, is chief medical officer, McKesson Specialty Health and the US Oncology Network.

Address for correspondence:

Michael V. Seiden, MD, PhD

10101 Woodloch Forest Dr.

The Woodlands, TX 77380


*The views and opinions expressed are those of the author and do not reflect those of McKesson Specialty Health, the US Oncology Network, or McKesson Corporation.


Special thanks to Sean Seamans and Wendy Brauner for helpful comments.


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