By Gesa Junge, PhD
Part 1 of this post described passive immunotherapies like antibodies and cytokines, but there are also active immunotherapies, which re-target our immune system towards cancer cells, for example cancer vaccines. These can be preventative vaccines, offering protection against cancer-associated viruses such as Hepatitis B (liver cancer) or Human Papilloma Virus (HPV, cervical cancer). The link between HPV and cervical cancer was first described in 1983, and a vaccine was approved in 2006. By 2015, the incidence of HPV infections in women under 20 had decreased as much as 60% in countries that had 50% vaccination coverage, although it may still be too early to tell what the impact on HPV-associated cancer incidence is. There are also other factors to consider, for example screening programmes are also likely to have a positive impact on HPV-associated cancers.
Vaccines can also be therapeutic vaccines, which stimulate the immune system to attack cancer cells. To date, the only cancer vaccine approved in the US is Provenge, used for the treatment of metastatic prostate cancer. For this therapy, a patient’s white blood cells are extracted from the blood, incubated with prostatic acid phosphatase (PAP, a prostate-specific enzyme) and granulocyte macrophage colony stimulating factor (GM-CSF) in order to produce mature antigen presenting cells which are then returned to the patient and search and destroy tumour cells.
Many other therapeutic cancer vaccines are in development, for example OncoVax, which is an autologous vaccine made from a patient’s resected tumour cells. OncoVax has been in development since the 1990s and is currently in phase III trials. Another example is GVAX, an allogenic whole-cell tumour vaccine currently being studied in phase I and II trials or pancreatic and colorectal cancer. As an allogenic vaccine, it is not made from the patient’s own blood cells (like an autologous vaccine), and it does not target specific antigens but rather increases the production of cytokines and GM-CSF.
Another therapy which is based on re-programming the patient’s immune system is adoptive T-cell transfer. As with some cancer vaccines, a patient’s T-cells are isolated from the blood, and the cells with the greatest affinity for tumour cells are expanded in the lab and the re-infused in the patient. A recent modification of this technique is the use of chimeric antigen receptor (CAR) T-cells, where the T-cell receptors are genetically engineered to be more tumour-specific before re-infusion. This approached was especially promising in chronic lymphocytic leukaemia, where some patients experienced remissions of a year and longer. Later, CAR T-cells were also tested in acute lymphocytic leukaemia, where response rates were as high as 89%.
Finally, a new class of cancer drugs called immune checkpoint inhibitors has been making headlines recently, some of which are now approved for the treatment of cancer. Immune checkpoints are part of the mechanism by which human cells, including cancer cells, can evade the immune system. For example, the programmed cell death (PD) 1 receptor on immune cells interacts with PD1 ligand (PDL1) on cancer cells, which inhibits the killing of the cancer cell by the immune cell. Similarly, CTLA-4 is a receptor on activated T-cells which downregulates the immune response.
The first checkpoint inhibitor was an antibody to CTLA-4, ipilimumab, which was approved for the treatment of melanoma in 2011. PD1 antibodies such as pembrolizumab and nivolumab were only approved in 2014, and the only PDL1 antibody (atezolizumab) in 2016, so it is difficult to tell what the long-term effects of checkpoint inhibitor treatment will be. Numerous checkpoint inhibitors are still undergoing trials, most of the advanced (phase III) ones being targeted to PD1 or PDL1. However, there are other compounds in early trials (phase I or II) that target KIR (killer-cell immunoglobulin-like receptor) which are primarily being studied in myeloma, or LAG3 (lymphocyte activation gene 3), in trials for various solid tumours and leukaemias.
Immunotherapies all come under the umbrella of biological therapies. Biologics are produced by organisms, usually cells in a dish, unlike synthetic drugs, which are manufactured using a chemical process in the lab. This makes biologicals more expensive to manufacture. Ipilimumab therapy, for example, can cost about $100 000 per patient, with pembrolizumab and nivolumab being only slightly less expensive at $48 000 – $67 000. This puts considerable financial strain on patients and insurance companies. From a safety perspective, biologicals can cause the immune system to overreact. This sounds odd, as the whole point of immunotherapy is to activate the immune system in order to fight tumour cells, but if this response gets out of control, it can lead to potentially serious side effects as the immune system attacks the body’s organs and tissues.
All of these therapeutic approaches (antibodies, interleukins, vaccines, and checkpoint inhibitors) are usually not used alone but in combination with each other or other chemotherapy, which makes it difficult to definitively say which drug works best. But it is safe to say that collectively they have improved the lives of a lot of cancer patients. If you are interested in finding out more about the fascinating history of immunotherapy, from the discovery of the immune system to checkpoint inhibitors, check out the CRI’s timeline of progress on immunology and immunotherapy here.