Immunotherapy

The need for more effective and targeted therapy for cancer has always been in the minds of researchers and doctors looking after patients with cancer. The traditional methods of treating cancer, i.e. surgery, radiation and chemotherapy, have obvious limitations.

Surgery would not be effective in disseminated or widespread diseases, while radiation and chemotherapy cause 'collateral damages' due to effects on normal cells while killing off cancer cells. Certainly, Immunotherapy- a treatment modality utilising and enhancing our immune system to prevent or fight off cancer, is a sound and attractive concept.

There is a general belief that failure of "immune surveillance" is a main contributory cause of cancer arising in an individual. There is also evidence that in many cancer patients, the immune system slows down the growth and spread of tumours. This means we need a competent immune system to prevent cancer and to prevent it from spreading once cancer has started.

The basis of cancer immunotherapy is to enhance the body's own immune system to fight off cancer, which sounds logical and simple in concept. Unfortunately, like most things in life, the real scenario proves to be far more complicated, and the quest for effective cancer immunotherapy has taken a long time however, slowly but surely, we are unravelling the mysteries.

What are the different types of cancer immunotherapy (CI) available now?

The cytokines and monoclonal antibodies used are not called drugs or medication but are labelled as biological immune response modulators (BIRMS), which include cytokines such as interferons, interleukins, colony-stimulating factors, and monoclonal antibodies plus the promising cancer vaccines. We can further categorise them as below:

• Immunostimulants 

  Immunostimulants are nonspecific agents that tune up the body's immune defences. There have been some successes with interleukin-2 (IL-2), a potent growth factor for T cells which has been used in kidney cancer and malignant melanoma, while alpha-interferon (IFN-a) is used for the treatment of chronic myeloid leukaemia and hairy cell leukaemia.

• Monoclonal antibodies

  Monoclonal antibodies are identical because they were produced by one type of immune cell; all clones of a single parent cell. Currently, most of the antibodies used are produced by recombinant DNA technology.

  The basis of monoclonal therapy is that different tumours have unique tumour antigens on their surfaces, and the identification of such antigens, such as CD 20 on lymphoma cells, and the production of anti CD20 antibody, i.e. Rituximab enables targeted cell death and selective killing of lymphoma cells. Indeed, the advent of Rituximab has changed the landscape of lymphoma treatment with improvement in response and survival of patients.

  Similarly, other monoclonal antibodies such as Trastuzumab (breast cancer), bevacizumab (bowel cancer), and alemtuzumab (chronic lymphocytic leukaemia) are making waves in cancer treatment.

• Immunotoxins and Radioimmunotherapy

  Monoclonal antibodies can be modified for the delivery of a toxin, radioisotope, cytokine or other active conjugates. Many of these conjugates have been tried with some success. Brentuximab vedontin is an antibody-drug conjugate that targets CD30, found on the surface of Hodgkin's Lymphoma and several other types of Non-Hodgkin's Lymphoma.

  Monoclonal antibodies against tumour antigens can also be coupled to radioactive isotopes. The goal with these agents is to limit the destructive power of radiation to those cells (cancerous) that have been 'tagged' by the attached monoclonal antibody toxicity. Ibritumomab tiuxetan is a monoclonal antibody against the CD20 molecule on B cells (and lymphomas) conjugated to the radioactive isotope yttrium-90 (90Y).

  The results in treating B cell lymphoma with radioimmunotherapy are encouraging, though the delivery of such an agent is somewhat cumbersome.

• Cancer Immunotherapy with T Cells (Allografts or Autografts of T Cells)

  T lymphocytes, such as cytotoxic T lymphocytes (CTL), are capable of killing target or tumour cells. However, priming them to act appropriately, i.e. to kill tumour cells and not other healthy cells, remains the challenge.

  The main reason why allogeneic bone marrow transplants (allografts) work is due to the post-transplant continual attacks on the tumour cells by T cells (graft versus tumour effect) seen in many patients. However, the accompanying graft versus host reaction can be severe enough to result in significant mortality and morbidity to the transplant recipient.

  The same effect of such immunological attacks on tumour cells can be harnessed by donor lymphocyte infusion. This is a 'double edge sword' and needs to be used with extreme caution.

  There are also other exciting therapies such as CAR-T cell therapy and immune checkpoint inhibitors. Chimeric Antigen Receptor (CAR) T cell therapy involves giving patients large numbers of T cells that have been genetically engineered to locate and attack cancerous cells.

• Immune checkpoint inhibitors (ICPI)

  One of the stars of immunotherapy against cancer is the immune checkpoint inhibitors. They are capable of blocking proteins (such as PD1 and PDL1) that stop the immune cells from attacking cancer cells. The immune cells involved are the T cells, which are rendered inactivated by proteins produced by cancer. Hence, they reverse T cell suppression and induce anti-tumour responses.

• Bispecific Antibody (BITE) Therapy

  BiTE (bispecific T-cell engager) therapies link endogenous T cells to tumour-expressed antigens, activating the cytotoxic potential of a patient's own T cells to eliminate cancer without genetic alteration of the T cells. Bispecific antibodies act as a go-between, recognising and attaching to cancer cells and joining them to the immune system’s T cells. That cancer cell-to-T cell attachment results in the T cells attacking cancer cells.

How do they work to kill cancer cells?

The T cells are one of the key players in our immune system that help us guard against bacterial/viral infection, and when turned on or become activated, they can recognise and destroy foreign invaders and cancer cells as well. There are proteins on the T cells that turn on or turn off their actions, and these are known as the checkpoints.

Some tumours are capable of producing checkpoint proteins that help them become shielded from the T cells that are turned off. Drugs that block checkpoint proteins are called checkpoint inhibitors. They stop the proteins on the cancer cells from pushing the stop button. This turns the immune system back on, and the T cells can find and attack the cancer cells.

How are these drugs administered?

They are given intravenously - using a drip straight into the bloodstream. The infusion time is over 30 minutes, and the drug is repeated every 3 weeks.

What are the strengths of immunotherapy?

The most appealing point of Cl is that this is potentially a targeted therapy; hence, the side effects to normal cells would be considerably less. Some chronic myeloid leukaemia patients with relapsed disease post bone marrow transplant managed to attain long-term survival after donor lymphocyte infusion.

Because the side effects are different from conventional chemotherapy, the combination of cytotoxics and immunotherapeutic agents such as Rituximab has improved the outcome of lymphoma patients without additional side effects. As the safety profile is favourable, Cl can be given in repeated courses, unlike cytotoxics which are limited by their cumulative toxicities.

What are the weaknesses or problems of immunotherapy?

The main problem is likely to be the need for time for the immune system to respond to Cl; and in some patients with cancer which behaves like a runaway train, e.g., Burkitt's lymphoma, time is what the patients do not have.

Cl is unlikely to work in a big volume tumour, hence the tumour needs to be debulked (reduced in size) or becomes under control before CI has a chance to work. Cl is costly, and the price is not likely to reduce in the near future. Monoclonal antibodies are very expensive. This is even more so for personalised vaccines.

Are immunotherapies devoid of side effects?

A resounding No. Any form of treatment can potentially give rise to side effects. Even taking paracetamol can rarely cause severe allergic reactions. Rituximab commonly gives rise to infusion reactions which are manageable.

The side effects of immunotherapy differ from conventional treatments like chemotherapy, and we have to learn about them (both short-term and long-term) and deal with them accordingly. For instance, we now know that the use of chemo-immunotherapy in treating non-Hodgkin’s lymphoma can cause potentially fatal hepatitis B virus activation. This problem is prevented by concurrent antiviral therapy.

How does Cl fit into our patient's treatment plan? Can a patient ask for immunotherapy first before following established treatment, or can Cl be the sole form of treatment?

Cl with monoclonal antibodies can be used in induction (initial treatment), or it is used to consolidate the treatment; and, in some instances, to remove any minimal residual disease.

Cell-based immunotherapy remains experimental and is likely to be offered in a setting of clinical trials. Very rarely, Cl is used as a sole form of therapy.

The patient, together with the attending doctor, should weigh the benefit versus risk equation and also the cost-effectiveness of the planned treatment. In other words, one should get into a treatment plan with eyes wide open. When a treatment sounds too good to be true, it usually is.