Immunotherapy has been emerging as the targeted cancer therapy in global healthcare. Apart from the conventional surgery, radiation and chemotherapy, physicians are targeting to boost the patient’s body immunity to fight out the disease. This can be achieved either by using substances formed in our body or the ones created in the laboratory. Immunotherapy helps the body to recognize cancer cells and attack them immediately thus creating a universal treatment response system.
Our body immunity system acts as surveillance to cancer cells to protect our body by destroying the cancer cells. But cancer cells can dupe a deficient immune system or hide from it making its entry to the body for further destruction. For many types of cancer, this has a great role in progression.
The objective of Immunotherapy is to reinforce the defense mechanism not only to destroy cancer cells but also check hiding of cancers. Another effective application of immunotherapy is in palliative care that helps in improving the patient’s quality of life.
Overview of Immunotherapy treatments:
Common types of immunotherapy include:
Monoclonal antibody therapy:
Monoclonal antibodies made in the laboratory can be used in targeting cancer cells. This targeted therapy has been approved for treating:
- metastatic colorectal cancer with the Nivolumab drug
- Brain cancer
- Breast cancer
- Chronic lymphocytic leukemia
- Ovarian cancer
- Prostate cancer
- Lung cancer
- Stomach cancer
- Hodgkin’s lymphoma and non-Hodgkin’s lymphoma
These antibodies work by releasing brakes on the immune system so that it can attack and destroy other cancer cells. There are certain pathways PD-1/PD-L1 and CTLA-4 through which cancer can bypass the immune system. The therapy is targeted to block these pathways with specific antibodies known as checkpoint inhibitors. This helps the immune system to detect and fight cancer by stopping or slowing its growth.
Some checkpoint inhibitors used for treating cancer are:
- Pembrolizumab ( Keytruda)
- Ipilimumab (Yervoy)
- Avelumab (Bavencio)
- Nivolumab (Opdivo)
- Durvalumab (Imfinzi)
- Atezolizumab (Tecentriq)
These also help in destroying cancer cells and are often given after or in combination with other cancer treatments. Currently, these are used to treat cancer in kidneys and skin including melanoma.
Two common non-specific immunotherapies are:
- Interferons that help the immune system to slow down or fight cancer
- Interleukins boost the immune system to produce cells to destroy cancer. Used in treating kidney cancer and melanoma.
Oncolytic virus therapy:
This therapy uses genetically modified viruses to destroy cancer cells. The US FDA in 2015 approved this therapy to treat melanoma that uses genetically modified herpes simplex virus.
T- Cell therapy:
T-Cells engineered in the laboratory are used to destroy cancer cells. T-Cells in our immune system help to fight infection. Engineered cells are provided with specific receptors that boost their fighting power. Known as Chimeric Antigen Receptor (CAR) T- Therapy, it has been effective in treating two types of cancers:
- Acute lymphoblastic leukemia
- Large B-cell lymphomas
Cancer vaccine exposes our body immunity system to an antigen making our immune system capable to recognize and fight that antigen or other related bodies. Prevention and Treatment vaccines are the two types of cancer vaccines.
As a preventative treatment, it helps in protecting from two types of virus:
- Human Papilloma Virus (HPV) responsible for cancer in cervix, genitals, anus and throat
- Hepatitis B responsible for liver cancer
As a treatment vaccine, it helps in fighting a type of prostate cancer.
Immune system modulators:
These enhance the immune system in a specific manner; that is the agents activate specific parts of the immune system while others affect the immune system in a general way.
How immunotherapy is given?
Immunotherapy is administered to patients either through an IV infusion, oral pills, topical application or intravesical application. The duration of immunotherapy depends on the type and stage of cancer, drug and its application process and the patient’s reaction. If the patient suffers from severe side effects, the treatment needs to be stopped midway.
Immunotherapy has shown marked improvement in treatment outcomes in many types of cancer creating a big impact on global healthcare. The reasons could be summarized as follows:
Targeted treatment for cancer:
Immunotherapy has special features giving more specific care to cancer making the treatment more effective.
Effective for many different types of cancer:
This has been more effective in treating patients with certain types of cancer resistant to chemotherapy and radiation, for example, melanoma.
Increasing the possibility of long-term cancer remission:
It can “train” our body’s immune system to recognize as well as remember the characteristics of cancer cells. This “immunomemory” power helps in long-term cancer remission.
Reinforces other cancer treatments:
Chemotherapy, for example, can be more effective if combined with immunotherapy drugs.
Clinical studies on long-term overall survival rates suggest that the beneficial effects of immunotherapy continue for a long time even after the completion of the treatment. Even if the treatment has to be stopped midway owing to side effects, the patients continue to get the same benefits as those taking the treatment for a longer time.
Unlike chemotherapy, immunotherapy always does not require completion of the course. Researchers say, the body’s immunity system gets trained during the short term therapy and can fight cancer.
Immunotherapy may not cause similar side effects:
Chemotherapy and radiation often damage healthy tissues while killing cancer cells. With immunotherapy, this probability does not exist.
The success of immunotherapy in improving survival rates:
Melanoma (skin cancer):
It is one of the immunogenic cancers that can be successfully treated with immunotherapy. Once deemed untreatable at the metastatic stage, melanoma is responding to immunotherapy drugs dramatically improving the survival rates.
Chances of long term survival are over 50%. In a study, it was found combination therapy of two immunotherapy drugs either stopped or reversed cancer progression in more than 50% of participants for 5 years or even more. Prior to immunotherapy, the survival of melanoma patients was counted in months or maximum a year.
The same study showed 3/4th of the patients receiving combination treatment no more needed routine treatment; this gives hope for a cure. Melanoma is the most threatening form of skin cancer that spreads rapidly. Researchers are hopeful of more such combination therapies in the next decade to improve the survival of 80% advanced melanoma patients.
Immunotherapy has been promising in improving survival rates of cancer considered untreatable. Pembrolizunab, the immunotherapy drug has helped over 15% of advanced non-small cell lung cancer survive for a minimum of five years, and 26% of patients with a specific protein in tumor cells cruised through the 5-year survival period, reports a team of UCLA researchers. Previously, it was just 5.5% for patients suffering from that type of cancer.
Lung cancer is leading in cancer related deaths in the US and worldwide. Only 1/3rd of patients experience a substantial reduction of tumor with standard chemotherapy and they manage to survive just for one year on an average.
Immunotherapy is likely to occupy the center stage in breast cancer treatment especially those resistant to chemotherapy. A recent clinical trial showed combined immunotherapy and chemotherapy can up the survival chances of triple-negative breast cancer patients by 10 months reducing death or disease progression by 40%. A new form of treatment following this trial will be soon available with the UK’s NHS (National Health Service).
Immunotherapy: risks and side effects:
Immunotherapy has given new hopes in cancer treatment but it cannot be considered entirely risk-free. Side-effects are there; sometimes physicians are floored by unexpected outcomes. The revved-up body immunity may have different repercussions beyond the scope of physicians. Drugs used to enhance body immunity for attacking cancer cells can attack healthy tissues taking them as foreign bodies.
Immunotherapy related side-effects are common, can vary and affect almost any organ of the body. These can even be life-threatening. Mild to moderate side effects respond well to steroids. Physicians administering immunotherapy must be on a constant vigil as some patients might develop serious health problems.
Some likely side-effects are:
- Pain, swelling and soreness on the area of injection
- Severe allergic reactions which can be fatal at times
- Inflammation in the inner lining of the lungs, colon and heart muscle
- Cytokine Release Syndrome: This can be caused by CAR- T therapy. The symptoms are faster heart beat, fever, low blood pressure and skin rash. Patients may develop confusion, tremors and communication problems.
- Complicated diabetes with no previous history of diabetes. This is one of the unexpected side-effects.
- In 1 or 2 rare cases, it was found patients in a clinical trial for 5 months for immunotherapy developed tuberculosis.
Boosting immune response can be good for bad. Since immunotherapy treatments are in the nascent stage, there is no adequate evidence from clinical trials regarding effective management of side-effects. Since the drugs are newly developed, many physicians are not educated enough of their potential side effects and its management.
To bridge this knowledge gap, the American Society of Clinical Oncology and the National Comprehensive Cancer Network in 2018 released a set of guidelines regarding steroid use and timely discontinuation of immunotherapy to prevent complications from side effects.
Challenges and future trends of immunotherapy in global healthcare:
Immunotherapy is not applicable to all cancer patients. As of today, it is effective for less than 50% of patients who opt for it. There is a partial response for some people. This means, the tumors may get smaller but do not go away completely. Physicians are still in the dark why immunotherapy does not work for all.
Immunotherapy faces a major challenge in its proven efficacy in treating most types of cancer and patients. Immune response varies a lot from patient to patient depending on various reasons. There is a need to:
- Find out additional biomarkers and cancer pathways
- Understand the heterogeneity of tumors
- Understand variability in cancer types, its growth, treatment record and immunosuppressive biology.
- Create customized patient-specific immunotherapy
Clinically significant biomarkers are not easy to identify:
Neoantigens or the tumor-specific antigens pose a limitation to cancer immunotherapy. These are expressed only by tumor cells. But tumor-associated antigens can be expressed by tumor and normal tissues, and if they are targeted it is likely to result in off-target toxicities.
Therefore, it is important to identify predictive biomarkers as it will help in selecting patients who will receive maximum benefits from immunotherapy and exclude those who will not.
Developing cancerous cells with specific mutations have a distinct advantage to proliferate as is seen by its dominance where local cells get displaced. It is therefore likely for all tumor cells to be biologically similar. Instead, it is found that cancer progression may rely on a relatively minor group of self-renewing cells. Genomic instability is inherent in cancer cells causing newer mutations owing to various external factors.
Developing resistance to immunotherapy drugs:
Tumor heterogeneity is closely associated with the development of resistant cancer cells owing to subclonal cancer cell proliferation. These contribute to failures in clinical immunotherapy.
Overly expensive immunotherapy drugs:
Immunotherapy in cancer is affordable to very few given the exorbitant cost of the drugs. This cost factor is preventing its wider application. It is affecting further drug development and treatment plans as researchers and physicians are not getting enough insightful data regarding the efficacy and side-effects, the two important aspects of drug therapies.
Managing side effects:
Even though it is said that immunotherapy side effects are less damaging than radiation and chemo, it can be dangerous for some patients. Not all patients show immune-related complications and those who develop such complications show wide variations in organs that are affected. Side effects can develop immediately after the application of immunotherapy or after a long time after the end of the treatment. Unexpected side effects also leave physicians in a big dilemma.
To broaden the applicability and enhance its efficacy and reduce toxicity:
There is a need for more targeted approaches. Research is on to define additional tumor antigens to support targeted therapy.
Enhanced application of personalized drug combinations to improve the efficacy:
These can be based on personal biomarkers or pathways that drive the patient’s tumor development.
More application in immunoprevention:
Immunotherapy in cancer has seen more rapid advances in treatments than its preventive strategies. Theoretically, immunotherapy has the potential to prevent cancer and its recurrence but this has largely been in the experimental stage. Cancer vaccines against HPV and Hepatitis B have seen great success. Immunotherapy treatments in future are likely to be more preventive.
More clinical trials in the future:
To make immunotherapy as the standard of cancer care, more clinical trials are needed. Patients are more likely to join these trials given the higher probabilities of tumor reduction and cancer recession period. More the number of clinical trials greater will be the benefits that could be reaped from immunotherapy. Currently, nearly 5% of cancer patients join clinical trials.
Immunotherapy treatment cost hitting the wall:
2011 was a watershed year for cancer medicine in the US when FDA just within five months approved a string of cancer immunotherapy treatments. The innovativeness and efficacy of these treatments were worth noticing but the cost was highly depressing. Each of these drugs cost over $100,000 per person when taken for a year. While mounting treatment cost is posing a big burden on global healthcare, immunotherapy costs seemed to add more pains instead of lessening it.
By 2014, the price of oral cancer immunotherapy medicines went past $135,000 per year nearly six times the cost of drugs approved in the 2000s. The most eye-popping price tag in cancer immunotherapy came up in 2017 that is $475,000 per patient for personalized child leukemia treatment.
This is four times more than the median household income in the US. Immunotherapy drugs, when applied in combination with other treatments, multiply the cost. Not all healthcare insurances offer cover for immunotherapy, even if it does so the co-pay amount is high enough to break the bank.
High costs in research and development and production do not justify this high price. Experts blame the free-market approach of drug companies. Many countries have better control in drug pricing by negotiating with drug manufacturers.
Lending a hand:
One notable example is the Glivec International Patient Assistance program where Novartis made the drug Imatinib (Glivec) for treating chronic myeloid leukemia available to the poorest in the developing nations. Over 50,000 people in 80 countries could benefit from 2.3 million monthly doses of this drug through this program.
Building up from this program, the Max Foundation running the imatinib access program has tied up with other manufacturers to make all the targeted immunotherapy for CML available in the market at very low prices.
Global healthcare needs more such initiatives to make immunotherapy more accessible and effective. Even a discount of over 50% in immunotherapy drug prices cannot make it affordable for the global population especially in developing nations where the cancer burden is noticeably high.
Immunotherapy is changing the frontier of cancer treatments; it is still in the evolutionary stage and yet to be revolutionary. It has not yet provided a universal cure for cancer which global healthcare is desperately looking for. Many cancer patients are not considered ideal for this therapy and there are many more patients who do not get benefit from it. Newer discoveries might address this issue in near future. Although immunotherapies have increased the patient survival rates appreciably, to what extent it is successful in providing the cure? More evidence-based studies in the coming few years might give us the answer.