Immunotherapy – promise of dissolving and melting tumours

In spring 2015, the New England Journal of Medicine’ reported the case of a patient with Stage IV metastatic melanoma – a disease considered close to untreatable. Although three growths in the skin had been surgically removed, one tumour under her left breast had grown deep into her chest wall. The 49-year old woman received a single treatment of an experimental combination of two drugs.
When she returned in three weeks for a second dose, the tumour had ‘kind of just dissolved’, according to Paul Chapman, the physician treating her at Memorial Sloan Kettering Cancer Center in the US.

Over one-fifth patients show complete response
The results were not an exception. 22percent of the 142 patients enrolled in the Memorial Sloan Kettering trial showed a complete response (with their cancer melting’ away), while 53percent had at least 80percent tumour shrinkage. However, there were downsides, too. Half the patients had side effects that were severe or life-threatening.
The drugs used in the trial were Yervoy (ipilimumab) and Opdivo (nivolumab). Approved by the Food and Drug Administration (FDA) for melanoma, the two belong to a small, new arsenal of drugs which supercharge the immune system to attack tumours. The process is known as immunotherapy, and brings together experts from several fields, ranging from oncology and immunology to cell biology and genomics.
Another well-known immunotherapy medication is Keytruda, sometimes called the Jimmy Carter drug’. Combined with surgery and radiotherapy, Keytruda has halted recurrence of melanoma in the former US president, although the disease had spread to his liver and brain.

Single drugs work too
One analysis of 4,846 advanced melanoma patients treated with Yervoy alone found 21percent still alive after three years. Patients who make it to three years ‘do not die of melanoma,’ according to James Allison of the MD Anderson Cancer Center in Houston, Texas, who is widely credited with pioneering modern immunotherapy.
Meanwhile, beyond melanoma, the combination of Yervoy and Opdivo has also shown extraordinary potential in bringing about remission in advanced stages of non-small-cell lung cancer, a leading cause of cancer-related mortality.

Leveraging the immune system
Leveraging the immune system to fight cancer, once little more than a medical dream, is becoming real. Using gene sequencing technologies to classify tumours, the immune system is now becoming primed with drugs and genetically-engineered cells.
The immune system itself consists of a biochemical network which defends the body against viruses, bacteria and other invaders. Cancer, however, finds ways to hide from the immune system, or block its ability to fight.
Immunotherapy seeks to help the immune system recognize cancer as a threat, and attack it.

The medical equivalent of atomic fission
At the moment, there are hundreds of immunotherapy clinical trials under way for almost all types of cancer, individually or combined with other treatments. Eventually, researchers hope to develop blood tests that allow for the early detection of cancer, determine which medicines can be effective and monitor the response in real time.
For some oncologists, immunotherapy is the medical equivalent of splitting the atom. John Heymach, a lung cancer specialist at MD Anderson, has described immunotherapy as a ‘complete game-changer.’ Several others concur. At an AACR press conference in 2015, Louis Weiner of Georgetown University observed: ‘We are in the middle of a revolution,’ and added that ‘I don’t think that is hyperbolic.’
The media too has leaped into the fray, latching on to the enticing concept of dissolving the tumours that physically embody one of humanity’s most intractable struggles against disease. Forbes’, for example, headlines an article: ‘Immune System Drugs Melt Tumours In New Study, Leading A Cancer Revolution.’

Checkpoint inhibitors
In practical terms, there are two contemporary approaches to immunotherapy.
The first (and more-widely used) method involves the use of drugs that block a so-called checkpoint’ mechanism used by cancers to shut down the immune system. This type of drug, known as a checkpoint inhibitor, is used to treat advanced melanoma, Hodgkins lymphoma and cancers of the lung, kidney and bladder.
The drugs work in 20-40percent of patients. In many such cases, the results are nothing short of spectacular, with prolonged remissions that persist, even after treatment is halted.

Checkpoint inhibitors harness T-cells, the white blood cells which could be described as the special force soldiers of the immune system. The T-cells can, however, run out of control and attack normal, healthy tissue, leading to autoimmune disorders like rheumatoid arthritis, Crohns disease and lupus. To avoid this, built-in brakes or checkpoints’ slow or shut down T-cells.
One type of checkpoint inhibitor stops T-cells from multiplying. Another weakens them and shortens their life span. The two drugs in the Yervoy-Opdivo study reported by the New England Journal of Medicine’ were both checkpoint inhibitors. Yervoy (ipilimumab) interferes with a molecule which switches off T-cells. Opdivo (nivolumab) prevents the death of T-cells.

Limitations with checkpoint inhibitors
Nevertheless, for the bulk of patients, checkpoint inhibitors do not show any results, or work for a while and then stop. In the Yervoy-Opdivo study, 126 of 142 patients did not see their cancer vanish entirely. One of the theories being researched to explain this setback is that other, to-be-discovered checkpoints are playing a role, and these would lead to new drugs that increase the scope of their effectiveness.
Meanwhile, harnessing an immune system in overdrive can also be very risky. As mentioned earlier, one out of two patients in the Yervoy-Opdivo study had side effects that were severe or life-threatening. In many cases, treatment for such patients needs to be discontinued.
Conversely, checkpoint inhibitors can also slow down vital glands such as the pituitary and thyroid, thus creating a lifelong need for hormone treatment. This can have an impact in other areas. For example, kidney transplant patients have suffered rejection after taking checkpoint inhibitors since the latter spurred their immune system to attack the grafted organ.
Checkpoint inhibitors can also take months to begin working, and sometimes cause inflammation that make scanner data show what may, confusingly, look like a growing tumour.

CART: personalized immunotherapy
The second approach involves highly personalized treatments known as CART, with the abbreviation arising from the use of a protein chimeric antigen receptor (CAR) to modify a T-cell, which are first removed from a patient, genetically altered to kill cancer, and then re-infused.
CARTs effectively synergize antibodies, which provide precision recognition of disease targets, with the power of T-cells. Unlike antibodies, however, the modified T-cells continue to multiply, serving as a living therapy.
In autumn 2013, researchers at Fred Hutchinson Cancer Research Center in Seattle launched a (preliminary) safety trial with a CART on a lymphoma patient, who had failed to respond to elevated doses of chemotherapy. It was the first trial of its kind to be conducted on a human. At the end of a fortnight, the patient was reported telling his physicians that the lymph nodes in his neck felt like ‘ice cubes melting.’

Beyond leukemia and lymphoma
CARTs have largely worked so far in cases of leukemia or lymphoma, albeit dramatically. However, Fred Hutchinson is also working on several other cancer types, including Merkel cell carcinoma, melanoma and several sarcoma subtypes.
Elsewhere, researchers at the University of Pennsylvania are working on a CART which targets mesothelin, a protein often encountered on the surface of tumour cells. Trials involve patients with serious ovarian cancer, epithelial mesothelioma, and pancreatic cancer.

Challenges with CART
Nevertheless, many practical challenges remain to be overcome with CARTs too. They require extensive research and refinement in the lab before patient trials. Production is also labour-intensive, requiring isolation of specific T-cells from a blood sample, followed by multiplication in an incubator and the use of a hemacytometer for counting, and then concentration in a centrifuge. Apart from fine-tuning their therapeutic effects, means to cost-effectively scale the technology will also be required to bring CARTs to market.
Like checkpoint inhibitors, CART therapy also has clinical limitations, even in its mainstay application in leukemia. 20-30percent of patients are not helped, and are likely to die.

Some way to go
In the final analysis, immunotherapy still has some way to go.
In spite of their often near-miraculous performance, immunotherapy drugs have worked in what is still a minority of patients.
Researchers are clearly aware that immunotherapy is unique, potent and extraordinary, but they cannot fully understand why – or yet control it adequately.

The risks of hype
Physicians also urge caution. Media-hype has led many patients to believe the age of chemotherapy is past. There are cases of unresponsive immunotherapy patients (or those suffering from unacceptable side effects) being switched back to chemotherapy, successfully. Though this may be due to a delayed effect of immunotherapy, it is too early to tell. Indeed, one explanation is that chemotherapy and immunotherapy may be working synergistically in such cases.

Industry too may need a reality check. Asset management companies like Piper Jaffray have forecast immunotherapy boosting the cancer treatment market to half a trillion dollars a year. This may of course face a collision with reality.
Yervoy costs over USD 120,000 ( Euro 110,000) for a four-course treatment, while Keytruda is billed at about USD 150,000 ( Euro 138,000) for a year. At current prices, the combination of Opdivo and Yervoy would result in an annual cost of USD 270,000 ( Euro 248,000). On their part, CART therapies may cost even more. How exactly these sums will be financed is indeed the trillion dollar question.