A New Method to Fight Cancer: The Body's Own Immune System

Evidence-Based Oncology, August 2014, Volume 20, Issue SP11

In early May, an article reported on an approach undertaken by scientists at the National Cancer Institute (NCI) in which immune cells were isolated from a patient to attack her cancerous cells; the patient was suffering from metastatic cholangiocarcinoma, which had spread from the patient’s bile duct to her liver and lungs despite chemotherapy.1 Following whole exomic sequencing, they identified CD4+ T helper cells (TH1) among the tumor-infiltrating lymphocytes (TILs) of the patient that recognize a mutation in the ERBB2IP protein expressed by the cancerous cells. The patient was initially subjected to an adoptive-cell transfer (ACT) with 25% mutation-specific TH1 cells, which shrunk the target lesions and stabilized the disease. However, when the disease progressed, the patient was administered >95% mutation-specific TH1 cells,

resulting in tumor regression.2 Although the patient’s tumors have not disappeared, the treatment provides proof of concept that the body’s own defense system can be harnessed and reprogrammed to attack a solid tumor.

Early Success With Leukemia and Melanoma

This approach has previously been used in treating patients suffering from leukemia and melanoma. Physicians at Memorial Sloan Kettering Cancer Center in New York treated 5 patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) with their own genetically modified T cells that expressed a CD19-specific CAR receptor.3 Although tumors in all 5 patients were rapidly eradicated, 2 patients died—1 from a blood clot and 1 in whom the cancer relapsed. However, 3 of the survivors received subsequent bone marrow transplants and have a good prognosis. The group recently published results from another study, this time with 16 patients with relapsed or refractory B-ALL who were treated with autologous T cells expressing CAR. The complete response rate was 88% among the 16 patients, most of whom subsequently received stem cell transplants. The group now plans to conduct a multicenter phase 2 study with the therapy.4

In 2012, the National Cancer Institute published a report on the success of ACT in melanoma patients.5 Three separate trials treated 93 melanoma patients with their own TILs, which had been grown out in the laboratory, along with the cytokine interleukin-2 (IL-2). Of the 93 patients, the tumor was completely eradicated (complete response) in 20, and 19 remained tumor-free for more than 5 years; some stayed tumor-free more than 8 years. Significant tumor shrinkage was observed in 52 patients. A similar trial at The University of Texas MD Anderson Cancer Center found that 25 of 50 patients had partial or complete tumor responses.

However, according to Michael Kolodjiez, MD, national medical director for oncology strategies at Aetna, although these treatments are very promising, they’d be difficult to adopt in the clinic. In an interview with Evidence-Based Oncology, Kolodjiez said, “CAR T cell therapies are complicated, their administration is complicated—consider what happened with Provenge. It’s definitely exciting therapy, but adopting it in the clinic can be challenging.”

ACT: Adverse Effects

The treatment is coupled with certain issues and side effects, as most cancer therapies are. The required lymphodepletion prior to the treatment, as well as the IL-2 administration, are associated with toxicity. A predicted consequence of rapid and potent antitumor immunity is the development of a generalized proinflammatory immune state. Furthermore, infusion of the large amount of T cells can generate an immune response, the cytokine release syndrome (CRS), that could potentially be fatal.5,6 CRS has been reported to occur several days to weeks after infusion of T cells. Additionally, both tumor lysis syndrome and macrophage activation syndrome have also been reported with the treatment.6 Efforts are ongoing to improve upon some of these procedural side effects of the therapy.

Artificial Immune Cells Join the Battle

A research group at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine, led by Jonathan Schneck, MD, PhD, has developed an innovative technique to attack a tumor: nanoscale artificial antigenpresenting cells (aAPCs). A graduate student in Schneck’s laboratory observed that treating the aAPCs with a magnetic field resulted in a clustering of T cells to which the aAPCs bind. Subsequently, naïve T cells were functionalized, which made the active T cells even more active. In turn, the normal immune response increased significantly. When injected into mice that were growing skin tumors, mice treated with nano aAPCs and then treated with a magnetic field presented significantly smaller tumors and longer survival compared with the control untreated mice.7

Schneck has pioneered a start-up, NexImmune, based on these nanoparticles; the company has trademarked the process as Artificial IMmune (AIM) Technology.8 The company claims that AIM aAPCs can be precisely engineered to orchestrate a polarized immune attack on the patient’s tumor. The immune cells can be readily designed and are not susceptible to suppression by Treg cells.

Refining the Traditional Approach

Traditionally, immunotherapy approaches can be classified into: monoclonal antibodies, cancer vaccines, and nonspecific immunotherapies.

Monoclonal antibodies reflect a more specific/targeted approach, since the antibody can be precisely targeted to a tumor-specific antigen.9 The current approach to improving the efficacy and safety of antibody treatment is the use of bispecific and even trispecific antibodies, combining parts of 2 (bi) or 3 (tri) antibodies together. A market research report released late last year identified several pharmaceutical companies (Roche, AbbVie, Pfizer, Sanofi, Amgen, Merck, and others) with ongoing phase

1 and 2 trials for bispecific antibodies.10 Meanwhile, a trifunctional antibody developed by TRION Pharma, Removab (catumaxomab), received approval in the European Union for the treatment of malignant ascites and is undergoing clinical trials in the United States (Table).

Cancer vaccines were developed with the goal of boosting the immune system to attack cancer cells, quite unlike the traditional vaccines administered to prevent infectious diseases. Cancer vaccines can include entire cancer cells, parts of cells, or just the antigens. A more personalized approach involves using a patient’s own immune cells and sensitizing them to the tumor cells in the laboratory to create a vaccine.11 An example of an FDA-approved cancer vaccine is sipuleucel-T (Provenge) for advanced prostate cancer (Table).

The nonspecific immunotherapy approaches include injecting cytokines, such as IL-2, interferons, and GM-CSF, into the body. Cytokines, produced by immune cells, regulate the growth and activity of other immune cells and blood cells, and can be administered either alone or concomitant with chemotherapy.11

Immune checkpoint inhibitors (both chemical inhibitors and monoclonal antibodies) are currently receiving much attention. Immune checkpoints are a part of the body’s defense system that prevents immune cells from attacking “self.” Cancer cells, however, use these checkpoints to circumvent an attack by the immune system, and drugs targeting these checkpoints have gained huge strides in the clinic. Some of the immune checkpoint proteins being targeted include cytotoxic T-lymphocyte antigen-4

(CTLA-4), programmed death 1 (PD-1), and programmed death-ligand 1 (PDL1). CTLA-4, expressed on the surface of T cells, keeps T cells from attacking other cells in the body. Cancer cells use this to their advantage to prevent an immune attack. Ipilimumab is a monoclonal antibody that binds to and inhibits CTLA-4 (Table). Although approved for melanoma, it is now being evaluated in combination with other antibodies and chemotherapy in the treatment of numerous other cancers. PD-1 is expressed

more often in T cells in inflamed tissues and tumors, where binding of the ligand PD-L1 prevents an immune response.11 Cancer cells have been found to overexpress

PD-L1 and efforts are ongoing to develop an antibody that effectively blocks PD-1 (Table).

Said Kolodziej, “There’s a lot coming out with the new checkpoint therapies, and although it’s very exciting, it’s still too early. Policy decisions regarding such novel therapies are not made (at Aetna) until the FDA has approved them. Additionally, we at Aetna also try to harmonize with the NCCN (National Comprehensive Cancer Network) treatment guidelines.” He added that Aetna has an evidence section led by the senior medical director, which helps draft company policies on coverage by amalgamating FDA approval, NCCN guidelines, and of course the available evidence on the drug or treatment. Initially, coverage will reflect the FDA label indications, which he said are the strongest indications based on evidence. “Expansion of coverage will take into consideration the NCCN recommendations. Once the drug is commercially available, it’s very important to ensure that the right person gets the right treatment.”

The Managed Markets

Early this year, The American Journal of Managed Care convened a panel discussion that brought together clinicians and payers to address the impact of the increased use of immunotherapy drugs in treating cancer in a managed care setting.12 The panelists agreed that immunotherapy, especially the newer checkpoint inhibitors, offer a promising approach in oncology. The drugs are currently being employed in refractory/relapsed patients, but the panel members expressed hope that immunotherapy would soon be used in curative and adjuvant settings.

Added Kolodjiez, “The sequence of therapies is important, but that’s not very clear yet. We need evidence for determining the sequence of administration of drugs. For example, consider melanoma: you have ipilimumab, B-RAF inhibitors, and the PD-1/PD-L1 inhibitors.” The FDA label could provide recommendations, but he suspects it will not.

The novel approach by researchers at the NCI and at Memorial Sloan Kettering is still at an early stage and considered “experimental” by insurance companies. Aetna’s policy bulletin states that ACT, using TILs or IL-2—treated lymphokine-activated killer cells, is classified as experimental and investigational therapy since there is not yet sufficient evidence that it is more beneficial than IL-2 alone.13 Cancer vaccines, specifically for melanoma and ovarian cancer, are also considered experimental therapy due to insufficient evidence of safety and effectiveness.14 Based on the available information for the drug, ipilimumab is considered necessary for malignant melanomas but experimental and investigational for all other cancers.15

Labeled as the “Breakthrough of the Year” in 2013 by Science magazine,16 immunotherapy holds immense promise as an effective treatment—but an expensive one. If expert predictions hold true, employer-sponsored insurance plans have to brace for a big hit, because it is estimated that immunotherapy drugs—expected to treat nearly 60% of all cancers—will cost $35 billion per year within 10 years.17 Payers, of course, are developing models and algorithms—including reimbursement incentives, guideline-based coverage, pharmacist medication consults, and early intervention—to help reduce the cost of treatment with these specialty drugs.17

When asked about determining the “value” of a particular treatment, Koldjiez said there are 2 important things that need consideration: “What is the outcome in terms of survival benefit, and the magnitude of the outcome in terms of symptom relief? Consider the PD-1/PD-L1 inhibitors as an example. Some patients have an extremely durable response and don’t need any more treatment for a long time, and the associated toxicities are minimal. But this is an exception and not a rule. In case of renal cell carcinoma patients, these inhibitors have proved extremely toxic and their effect does not last too long.” If a treatment is beneficial, says Koldjiez, the cost does not matter. The cost discussion, according to Kolodjiez, surfaces when the magnitude of benefit is small (a few weeks or months vs years). For treatments that provide greater benefit, there isn’t even a discussion.


Although the debate continues, an even-minded approach remains essential. Open conversation among patients, providers, payers, and the pharmaceutical industry will be what ultimately defines “value”: be it that of the drug or, more importantly, the patient’s life. References

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2. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641-645.

3. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38.

4. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25.

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7. Nanoparticles and magnetic fields train immune cells to fight cancer in mice [press release]. Baltimore, MD: Johns Hopkins Medicine; February 24, 2014. http://www.hopkinsmedicine.org/news/media/releases/magnetic_medicine.

8. The next generation of immunotherapy. NexImmune website. http://www.neximmune.com/ home. Accessed May 22, 2014.

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11. Cancer vaccines. American Cancer Society website. http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-cancer-vaccines. Accessed May 23, 2014.

12. Immunotherapy in cancer care: understanding the impact of shifting treatment paradigms in the managed care setting. Am J Manag Care. 2014;20(SP2):SP38-SP44.

13. Clinical policy bulletin: adoptive immunotherapy and cellular therapy. Aetna website. http://www.aetna.com/cpb/medical/data/600_699/0641.html. Accessed May 27,


14. Clinical policy bulletin: cancer vaccines. Aetna website. http://www.aetna.com/cpb/medical/data/500_599/0557.html. Accessed May 27, 2014.

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