This article reviews the recent and unprecedented acceleration in the understanding of cancer pathophysiology, which has led to the subsequent development of novel cancer immunotherapies. In part, this new direction in cancer treatment has been advanced by a greater understanding of individual patient genomics and has contributed to the realization of the so-called “precision medicine” era.
For decades, the various types of cancer have classically been treated with combinations of chemotherapy, surgery, and radiation depending on the type and stage of cancer. While this strategy led to great and historical success and cures for some types of cancer, significant limitations and relatively few treatment options remained for more advanced, metastatic, or treatment-resistant disease.
This article reviews the recent and unprecedented acceleration in the understanding of cancer pathophysiology which has led to the subsequent development of novel cancer immunotherapies. In part, this new direction in cancer treatment has been advanced by a greater understanding of individual patient genomics and has contributed to the realisation of the so-called “precision medicine” era.
Cancers develop through a combination of genetic and epigenetic changes that lead to cellular immortality. Simultaneously, these changes create new cell surface antigens, called neo-antigens, which should be recognised as foreign by the host immune system and then eliminated. However, tumours have evolved several mechanisms to evade immune detection including induction of tolerance, systemic disruption of T-cell signalling, and immune editing. The latter process is defined as a selective process in which tumour cells which are less immunogenic and more resistant to apoptosis (programmed death) go unrecognised and increase in number unchecked.
The concept of utilising an individual’s own immune system to treat cancer is not new, but has been relatively unsuccessful historically. While the above paragraph describes how tumours can evade the host’s immune system, it is well known that the immune system can be quite efficient at eliminating many tumours after early malignant transformation. This is termed immune surveillance. Thus, if new therapies could be directed at blocking the underlying mechanisms of tumour evasion this would allow the immune system to successfully perform its role in eliminating tumours and would represent a renaissance in cancer treatment based on immunotherapy.
That time has now arrived...
While there are many diverse directions in which immunotherapy technology is developing, this review will primarily focus on adoptive T-cell therapies and checkpoint inhibitors. Additional discussion will be provided on vaccines and oncolytic viruses.
Adoptive T-cell Therapies
There are two major directions of therapy in which the host’s T-cells are removed from the body, enhanced, and then re-infused back into the patient to treat the tumour. This strategy is not necessarily a new idea and has been attempted with some success for a number of years. However, now that tumour biology is better understood, the actual methodology is meeting with improved outcomes.
The first protocol involves removing a patient’s T-cells from blood or metastatic tumour tissue. They are then grown in the laboratory to very large numbers in enriched and stimulatory solutions to become tumour-infiltrating lymphocytes (TILs). Meanwhile, the patient undergoes concurrent treatment to reduce the number of remaining lymphocytes before the TILs are re-infused into the patient. Once re-infused, the TILs are directed to the original tumour cells and are stimulated to cause their destruction. This type of treatment has only been successful for treatment of melanoma, but in some cases up to 22% of patients responded for up to 82 months. The cost and time required for this treatment may limit its usefulness.
The second adoptive T-cell therapy which has been receiving a lot of attention of late is the use of engineered chimeric antigen receptor T- cells (CAR T-cells). While there has been some recorded success against B-cell tumours, melanoma, and certain types of sarcoma, there are concerns regarding safety (see below) and lack of a prolonged response. Nonetheless, this technology will receive significant on-going research and refinement.
Checkpoint Inhibitors
This novel therapeutic approach interrupts immune-inhibitory pathways which are activated by cancer cells. One target for checkpoint inhibitors is the CTLA-4 receptor which down-regulates activation of T-cells. By blocking this receptor T-cells are allowed to activate and then carry out their anti-tumour response. In 2011, the U.S. Food and Drug Administration (FDA) and the Therapeutic Goods Administration (TGA) in Australia approved the CTLA-4 inhibitor ipilimumab as treatment for metastatic melanoma. Its use has also been approved in New Zealand but it has not been approved for subsidisation under PHARMAC. Relatively few patients respond to this treatment, but those who do can have a sustained benefit with significant extension of life.
Another type of checkpoint inhibitor, the PD1-PD-L1 blocking agents, address a different mechanism of action by allowing the T-cells to proliferate, produce other cell mediators, and effect tumour cell destruction. This class of drugs includes pembrolizumab, nivolumab, and atezolizumab. These have been shown to be effective against various tumours including melanoma, lung, colon, head and neck, gastric, and renal cell carcinomas.
Vaccines and Oncolytic Viruses
Unlike vaccines designed to prevent infectious diseases, successful cancer vaccines must circumvent the immune tolerance induced by cancer cells. A technical hurdle in the development of these vaccines is the determination of the best stimulatory antigens to be used for immune system cell activation. It has been shown that co-administration of immune stimulants such as interleukin-2 (IL-2) improve efficacy.
The most successful vaccine-based cancer treatment to date is sipuleucel-T, which was approved by the FDA in 2010 for the treatment of metastatic prostate cancer. Its use can achieve a survival advantage of four months. However, this treatment has not been approved for use in Australia by the TGA due to its high cost as well as questions over its actual effectiveness. The results are modest, at best, and significant obstacles must be overcome in order for other vaccine therapies to become mainstay therapy for other cancers.
Theoretically, viruses represent the perfect vehicle to deliver very specific anti-tumour therapy. Viruses directed at tumours also favour selective replication in cancer cells, only with much less risk of normal cell involvement or destruction. Mechanistically, viruses can cause direct destruction of tumour cells through lysis and other innate immune system recruitment pathways.
One drawback of this treatment strategy is that the body’s immune system could remove the virus before it is able to carry out its anti-tumour activities. However, methods to circumvent this premature inactivation are available. To date, a modified herpes simplex virus type 1, talimogene laherparepvec (T-VEC), was approved in October 2015 by the FDA for use in advanced melanoma cases. T-VEC has not been approved for use in Australia. A significant limitation of this treatment is that it requires multiple injections over time directly into the tumour tissue. Clearly, based on anatomic limitations, not all tumours would be accessible to this approach. Ideally, future vaccine treatments would allow systemic administration.
The adoptive T-cell therapies, specifically the CAR T-cell treatments, have a well-defined side-effect and toxicity spectrum. Severe immune-mediated complications have occurred after CAR T-cell infusion. Due to the lifespan of T-cells, potential adverse effects could last up to 10 years. The most common CAR T-cell adverse effect is known as cytokine release syndrome (CRS). Symptoms can range from fever and fatigue to severe, multi-system organ dysfunction and disseminated intravascular coagulation. CRS can be treated, but it must be balanced by avoiding a reduction in the anti-tumour activity of the infused T-cells. Additionally, neurotoxicity and anaphylaxis may occur.
Checkpoint inhibitors have been associated with a number of specific inflammatory side-effects known as immune-related adverse events (irAEs). Generally, adverse events and the severity of those events are worse with the CTLA-4 inhibitors than with the anti-PD-1 therapies. Specifically, the CTLA-4 inhibitor ipilimumab has been associated with severe irAEs in up to 35% of patients.
Other common checkpoint inhibitor side effects include rash and diarrhoea with or without colitis. Elevated liver enzymes may also be observed and should be monitored while on treatment. Hypothyroidism and pituitary inflammation may occur as well, and TSH should be monitored during treatment, especially with ipilimumab. Finally, life-threatening pneumonitis can develop, but this serious complication occurs in less than 10% of treated patients.
There are multiple strategies being developed to mitigate the risk associated with immunotherapy treatment side-effects. It has been stated that just as precision medicine has changed cancer treatment a similar personalised approach must also be used to assess potential treatment toxicities.
Many insurance products and benefits are designed and based upon traditional risk stratification and expected outcomes from standard cancer therapies. The development of new treatments, including, but not limited to, immunotherapies, introduces several new elements with which underwriters, claims assessors, product developers, and medical directors will need to become familiar. The benefit of extended life and potential cures will be of great benefit to all affected by cancer. On the other hand, additional costs of treatment and implications for various product definitions will need to be assessed, e.g. terminal illness. While there may be some short-term increased uncertainty for insurers, there is potential for increased long-term opportunity.
The practice of medicine has recently entered a new golden age of cancer treatment innovation. No longer are clinicians limited by the traditional regimens of chemotherapy, radiotherapy, and surgery. While the full benefits, risks, and costs of these new treatments are yet to be realised, there is no doubt they have the potential to be game changers with regard to both short- and long-term morbidity and mortality outcomes.
For additional detailed reading, the author refers the reader to the excellent review article by Farkona et al listed below. The majority of information contained in this review was obtained from that reference. The author also wishes to thank Dr. Sheetal Salgaonkar (RGA), Mumbai, India for technical review and assistance.
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