A New Front on the War on Cancer: Immunotherapy

An excellent article from The Economist outlines the four traditional strategies for fighting cancer along with a new treatment strategy that is generating a lot of excitement. The four classic strategies are as follows:

1. Surgery (remove the tumor)
2. Radiation Treatment (kill tumor with radiation)
3. Chemotherapy (treat tumor with drugs that prevent general cell proliferation)
4. Targeted Therapy (treat tumor with drugs that specifically prevent cancer cells from growing/dividing)

The fifth strategy is immunotherapy which entails leveraging the body's immune system to fight the cancer. The immune system is designed to recognize non-self objects (e.g. foreign infectious viruses or bacteria) and then kill them. The problem is that cancer cells are derived from one's own cells and can be hard to distinguish from self cells. Pre-cancerous cells (i.e. cells "on the road to cancer") arise all the time, and the immune system is responsible for keeping them in check. Diseases that weaken the immune system (e.g. AIDS) increase the incidence of certain types of cancer. Inversely, practices that strengthen your immune system (e.g. exercise) are thought to provide protection against cancer.

The goal of immunotherapy is to enhance the immune response to fight against full-blown cancer that may be spreading throughout the body (metastatic). There have been efforts along these lines in the past. Most notably, Dr. Steven Rosenberg was one of the first (in the 1980s) to advocate immunotherapy against cancer. His approach was to combine high-doses of interleukin-2 (which regulates T-cell function) with tumor-infiltrating lymphocytes. Unfortunately this regimen did not have much success while being toxic to patients. More recently, some companies have explored the idea of a cancer vaccine in which high doses of tumor-specific antigens are injected into a person to try to elicit an immune response against those antigens just like one elicits an immune response against the measles virus by the measles vaccine. Finally, ultra high doses of the measles vaccine itself have been tested against some cancers in the hope that a general large immune response against any foreign agent may also attack cancer cells as collateral damage. The latter two approaches are still experimental, and their beneficial effects have not been demonstrated.

As mentioned above, one major challenge is that the immune system has trouble distinguishing cancer cells as "non-self" foreign invaders because they are derived from one's own somatic cells. A second significant problem is that cancer cells have devised strategies to evade the immune system:

"Cancer seems to use three strategies to evade the body’s defences, says Edward Bradley of MedImmune, a drug-development firm based in Maryland. One is to present itself to the body in such a way that the immune system fails to recognise it as something that should be killed. Another is to interfere with the abilities of T-cells, whose duty it is to carry out such killings and which, by hanging around for decades in the body, provide durable immunity to a given disease. Lastly, there are all sorts of ways in which the immune system as a whole can be suppressed."

The point of the current generation of immunotherapies is to help immune cells recognize cancer cells as the enemy and to prevent them from interfering with the T-cells, which are the immune cells most responsible for attacking tumors. The two most promising strategies are (1) CAR-T (chimeric antigen receptor T-cell) which helps T-cells recognize cancers by providing the T-cells with a synthetic receptor specific against tumor antigens, and (2) immune checkpoint inhibitors (e.g. PD-1 inhibitors) that prevent tumor cells from inhibiting the function of T-cells.

At the most recent annual meeting of the American Society of Clinical Oncology (ASCO), there was a plethora of new exciting data from the immune checkpoint inhibitors:

"A lot of tumour cells express proteins on their surfaces—so-called “checkpoint” proteins—that bind to complementary molecules on T-cells in a way that persuades the immune system to leave the tumour alone. In 2011 Bristol-Myers Squibb, a drug company, introduced a product called Yervoy, an antibody that binds to one of these deceptive checkpoint proteins, CTLA-4, and thus thwarts its attempts to fool the immune system. Yervoy was the first drug to prolong the lives of patients with melanoma; compared with the standard treatment it reduced their risk of death by about a third. Excitingly, tumours in a small number of patients went away and did not come back. Last year Merck, another big drugs firm, brought out Keytruda, an antibody that targets a checkpoint protein called PD-1 in a similar way. After a year, 74% of those who received Keytruda were still alive, compared with 58% for those on Yervoy. Bristol-Myers Squibb has since developed Opdivo, another PD-1 drug; Roche and AstraZeneca, two more drug companies, have similar treatments in the pipeline."

Even more exciting results were reported from combining two different checkpoint inhibitors. For example, "progression-free survival in melanoma (in other words, the amount of time during which a patient’s cancer did not become worse) was 6.9 months for those on Opdivo alone and 2.9 months for those taking only Yervoy. Patients given both, though, posted an average time of 11.5." In another example, "for late-stage lung cancer, where the best treatment is chemotherapy, the fraction of people still alive after five years is typically just 5%. Combinations of immuno-oncology drugs have boosted this to between 20% and 30%."

The second major new immunotherapy is CAR-T (chimeric antigen receptor T-cell). The idea is to use gene therapy to add a special receptor to T-cells that will make them target tumor-specific antigens on cancer cells (Figure 1). The chimaeric receptor will enhance the ability of the T-cell to recognize and kill the cancer:

"One theory is that some tumours may be employing Dr Bradley’s first avenue of escape; instead of (or as well as) trying to hide from a T-cell response, they try to avoid provoking such a response in the first place. Juno Therapeutics, in Seattle, hopes its CAR-T therapy will close that route off, too. This involves extracting T-cells from a cancer patient and modifying them with gene therapy so that they produce a tumour-recognising protein on their surfaces. These cells are multiplied in a dish and put back into the patient’s body."

In particular, the CAR-T treatments have focused on the CD19 antigen which is found on B-cell leukemias and lymphomas (TheScientist):

"Founded just a year earlier, the Seattle-based company now has four CD19-targeting CAR T-cell therapies in trials. The premise is simple: extract a patient’s T cells from blood and train them to recognize and kill cancer by modifying them with a viral vector to express an artificial, or chimeric, receptor specific for a particular cancer-associated antigen—in this case, CD19, an antigen expressed in B-cell–related blood cancers—then reinfuse the cells back into the patient."

The results have been very promising. At the ASCO meeting two groups presented data on B-cell lymphomas (Matthew Herper). A collaboration between a group from UPenn and the company Novartis showed the following:

"The Penn group is presenting data from 19 patients with NHL that had failed treatment with chemotherapy and the cancer drug Rituxan. These patients have no treatment options and often fail bone marrow transplants. In one type of NHL, called diffuse B cell lymphoma, 6 of 12 patients saw their disease reduced (called a response), including five who had a complete response, meaning that the cancer became undetectable. In a second type, called follicular lymphoma, all seven patients had a response, and in six patients it was a complete response. Schuster says the complete responses are “durable.” He adds: “I could actually see this replacing transplant in lymphomas.”

A lot of the best results for CAR-T are against blood cancers. It remains to be seen whether this treatment will work as well on solid tumors. However one can imagine combining immune checkpoint therapeutics (i.e. anti-PD-1 monoclonal antibodies) with CAR-T in the mother-of-all combination therapies against a wider array of cancers including refractory solid tumors. It would be interesting if the two have an additive or even synergistic effect when used together on these hard-to-treat tumors.

A click-baitish headline from the BBC asks "Have we cured cancer?" The answer is still "No." However by launching a new front (immunotherapy) on the war on cancer we are increasing the number and power of weapons (treatments) at our disposal. This battle will be fought cancer by cancer, case by case, in grinding trench warfare until we eventually achieve victory. Immunotherapy will be a very important weapon in this battle.

Figure 1. The basics of CAR-T. "By modifying T cells to express chimeric antigen receptors (CARs) that recognize cancer-specific antigens, researchers can prime the cells to recognize and kill tumor cells that would otherwise escape immune detection. The process involves extracting a patient’s T cells, transfecting them with a gene for a CAR, then reinfusing the transfected cells into the patient" © LUCY READING-IKKANDA.