A new strategy in the fight against cancer is to counteract the self-tolerance of the patient's immune system against tumours. The development of drugs for this therapeutic strategy was one of the most cutting-edge issues discussed at a recent symposium of the American Society of Clinical Oncology.

These drugs are "PDL-1 inhibitors", acronym for Programmed Death Ligand-1, a protein that interacts with a receptor on the surface of many, if not all cells, be they healthy or malignant. The result is cell death. Apoptosis is a truly complex process with multiple closely regulated checkpoints. Although this may be an oversimplification, these drugs lock onto PDL-1 and counteract its capacity for bonding with a specific receptor. This non-activation of the PD-1 receptor allows the T-cells to remain functional, blocking the signalling pathways of the cells that result in apoptosis. When this happens to the T-cells, it allows them to continue fighting against malignant cells. In other words, tolerance to the tumour is counteracted.

Research is showing that most tumours have a predictive marker for susceptibility to this therapeutic strategy. Preliminary studies have focused on melanoma and lung cancer, but recent studies show that the above findings can be extrapolated to other malignancies, such as colon and rectal tumours, and prostate cancer.

As of August 2015, three PDL-1 inhibitors had been marketed: Keytruda® (pembrolizumab ^[1]) by Merck, Opdivo® (nivolumab ^[2]) and Yervoy® (ipilimumab ^{[3 ]}) both by Bristol Myers Squibb.

PDL-1 is considered to be a “cell marker”. The works of Edward A. Boyse and Lloyd Old ^[4] at Memorial Sloan-Kettering Cancer Center during the 1960s must be mentioned at this point. Their research led to the discovery of a group of receptor proteins with an immunoglobulin structure. These proteins are located on the surface of both healthy and malignant cells. When expressed on the surface of T-cells, these cell markers have the ability to activate or deactivate immune response. During this research, these cell markers served as a conceptual framework for the classification of types and subtypes of cancer, but, most importantly, they also served as a starting point for the development of antibodies against cancer.

Nivolumab and pembrolizumab are IgG4 humanized monoclonal antibodies. Ipilimumab is a monoclonal antibody against Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA4). All three drugs were approved for the treatment of melanoma. Moreover, Opdivo® (nivolumab) were authorised in March 2015 for the treatment of a kind of squamous cell cancer, which makes up approximately one out three lung cancers.

A study published in May 2015 showed that nivolumab prolongs the survival of patients with non-squamous cell lung cancer. In this study, all patients were treated with platinum compounds. Based on this study, which included 582 patients, Bristol Myers Squibb will apply for the authorization for the use of nivolumab in non-squamous cell lung cancer.

Another study, presented at the symposium of the American Society of Clinical Oncology, in 2015, showed that nivolumab caused the collapse of 19% of liver tumours. This finding is important. Today, there is only one drug available for the treatment of liver cancer: Nexavar (sorafenib ^[5]), which was developed by Bayer and Amgen.

Another PDL-1 inhibitor, pembrolizumab, attained the collapse of 25% of head and neck cancers.

There are other ongoing clinical trials that have shown that PDL-1 inhibitors may be effective in patients with others types of cancer, such as that of the kidney, prostate and pancreas.

Why do PDL-1 inhibitors work in some cancers and not in others? A theoretical model suggests that an accumulation of mutations allows the patient's immune system to react against the tumour. The fact that the best results have been achieved so far with melanoma and lung cancer could be because the accumulation of mutations makes the recognition of malignant cells by immune system feasible.

Other cancers particularly susceptible to treatment with inhibitors PDL-1 are those that develop in patients with Lynch syndrome, a genetic pathology that increases susceptibility to developing tumours due to the impossibility of repairing errors in cell replication. Lynch syndrome accounts for about 5% of all tumours of the colon and rectum, but also of other malignancies. Genes MLH1, MSH2, MSH6 and PSM2 are involved in the repair of errors during the replication of DNA strands. Lynch syndrome is inherited as an autosomal dominant disorder. Pembrolizumab (Keytruda®) was studied in 29 patients: the tumours shrank in 4 out of 10 “Lynch-positive” patients, but not in any of the 19 “Lynch-negative” patients. A genetic test for Lynch syndrome has been marketed. However, the high cost of treatment ($150,000 annually for Keytruda® and Opdivo®) makes it imperative to develop a test that discriminates between patients who benefit from these treatments, and those who do not. A test of this nature implies scientific and ethical issues. On one hand, it is not possible for the oncologist to decide to use these drugs solely considering such a restrictive criterion; and, on the other hand, it is difficult for oncologists to withdraw or establish a treatment even if the benefit expected is limited.

The urgent need for a marker can be inferred from a study published in New England Journal of Medicine, in which 945 treatment-naïve patients were divided randomly into three groups: one treated with ipilimumab, another with nivolumab, and the other with both drugs. All patients had unresectable melanoma stage III or IV. The progression of the disease slowed down for 11.5 months in the group treated with both drugs, 6.9 months in the nivolumab treated arm, and 2.9 months in the group treated with ipilimumab. The incidence of adverse effects (especially diarrheoa and colitis) was significantly higher (55%) during combined therapy, compared to monotherapy with ipilimumab (27.3%), or nivolumab (16.3%). According to some oncologists, treatment with nivolumab alone can be as effective as combined therapy (ipilimumab and nivolumab), but the selection of patients requires an unambiguous clinical marker, and the PDL-1 is obviously the best candidate.

Another possible "marker" could be mutation clusters. The accumulation of mutations makes the cancer more susceptible to treatment with PDL-1 inhibitors. This fact has been shown in studies with ipilimumab (Yervoy®) in the treatment of cancer of the colon and rectum.

A third "marker" is the degree of infiltration of T-cells (the "infantry" of the immune system) in neoplastic tissue. This infiltration is predictive of the response to PDL-1 inhibitors. If the tumour is only slightly infiltrated by T-cells, the tumour’s response to these drugs will be much more limited. NanoString Technologies is developing a test that quantifies the genes involved in immune response.

Insurance companies and public and private health systems face a serious economic problem. The main argument against PDL-1 inhibitors is that the clinical trials with these drugs are carried out on only a small number of patients. This fact is illustrated in a study ^[7] in which nivolumab and docetaxel were compared in the treatment of lung cancer. No statistically significant differences were observed, but the cost of treatment with nivolumab was $60,000 as opposed to $6,000 with docetaxel.

Perhaps the research into drug therapy for the treatment of cancer is changing. Do not forget that chemotherapy with multiple drugs was a paradigm shift when, in the mid-1950s, Emil Frei III and Emil J. Freireich changed treatment protocols for leukaemia in children. They started the treatment using several drugs to attack the tumour from different flanks, using lower doses of each drug in order to reduce their iatrogenic effects. This strategy, which soon became the norm in the treatment of cancer, reduced mortality caused by child leukaemia from almost 100% in the mid of 1950s to about 40% a decade later. Today life expectancy for leukaemia patients is similar to the life expectancy of a healthy person.

One of those children who benefited from Emil Frei III’s strategy ^[6] was Edward M. Kennedy, son of the senator from Massachusetts. In 1973, he lost his leg as a result of suffering from osteosarcoma. At that time, he was 12 years old, now he is 53, and is a lawyer and advocate for disabled people in New Haven, New York.

Cancer research is a hugely demanding task, requiring tactics and strategy as on any battlefield.

Bibliography

1.-    Robert C., et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised close-comparison cohort of a phase 1 trial. Lancet 2014; 384(9948): 1109-17.

2.-    Deeks ED. Nivolumab: a review of its use in patients with malignant melanoma. Drugs 2014; 74: 1233-9.

3.-    Cameron F., et al. Ipilimumab: first global approval. Drugs 2011; 71: 1093-1104.

4.-    López-Tricas, JM. Obituario de Lloyd J. Old. http://www.info-farmacia.com/obituarios/obituario-de-lloyd-j-old. In: www.info-farmacia.com. Consult: August 2015 (Spanish).

5.-    Keating GM, Santoro A. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs 2009: 69: 223-40.

6.-    López-Tricas, JM. Obituario de Emil Frei III: promotor de la quimioterapia. http://www.info-farmacia.com/system/app/pages/search?scope=search-site&q=Emil+Frei+III. In: www.info-farmacia.com. Consult: August 2015 (Spanish).

7.-    Julie Brahmer MD., et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: 123-135.

Zaragoza (Spain), August, 10^th, 2015

 

López-Tricas, JM MD

Hospital Pharmacist

Zaragoza (Spain)