charting the history of immunotherapy, cancer treatment's fourth pillar

During Ancient Egyptian times, there were numerous accounts of tumours disappearing or regressing following infection with a fever. This led Greek physician, Claudius Galen (130-200 AD), to write for the first time that cancer might evolve from inflammatory lesions – it is from Galen that we derive the word oncology as he used the Greek work for swelling, oncos, to describe tumours.

After noticing that erysipelas infections in cancer patients led to tumour regression, two German physicians, F Fehleisen and W Busch, intentionally infected cancer patients with this bacterial disease and observed that this caused a noticeable shrinkage of their tumours. Thereby, suggesting that the immune system had a modulatory role in treating cancer. Fehleisen then figured out which bacteria causes erysipelas, Streptococcus pyogenes.

New York surgeon William B Coley also noticed that after an erysipelas infection his sarcoma patients saw a long-term tumour regression Other case reports showed patients experienced spontaneous remission after an acute bacterial infection, so he began a 40-year project where he injected mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens bacteria, known as ‘Coley’s toxins’ into patients with inoperable tumours. 

He reported that more than 1,000 patients had experienced remission and been cured of cancer. This is often viewed as the first immune-based treatment for cancer and has earnt Coley the title of ‘Father of Immunotherapy’. 

Viruses also emerged as a potential trigger for immune responses against tumours; in 1896, American doctor George Dock documented tumour remission following a severe influenza infection in leukaemia patient.

Following on from Paul Ehrlich’s work on antibodies and how they combine with antigens in the late 1800s, scientists carried out research into tumours removed from animals. These studies discovered "tumour-associated antigens" (TAAs), which the immune system could potentially recognise and form the basis of therapies. In the 1950s, researchers began to search for targetable TAAs and antibodies that can could bind to them. 

This occurred in the context of hesitancy and scepticism in the medical community about the use of immunotherapies, because there was a lack of understanding about their mechanism of action; instead chemotherapies, which started to be approved in the 1940s, became the preferred choice, alongside the traditional surgical approach.

In 1957, the interferon - a cytokine produced by white blood cells - was discovered; there is dispute about the scientists who should be credited. It was initially viewed as useful against viruses, but over the next few years, various researchers found it to also be effective against cancer in mice models. 

The idea of using bacterial infections as effective approach against cancer re-emerged in the 1950s when Lloyd Old and his team carried out a study that showed the anti-tumour effects of tuberculosis-related BCG bacteria in mice with bladder cancer. In the 1970s, further studies were carried out into the promise of this bacteria in melanoma remission. 

The BCG vaccine was approved by the US Food and Drug Administration (FDA) in 1990 for bladder cancer; it remains the standard of care in that indication to this day.

While seeking to grow T cells in a culture, Robert Gallo and his team at the US National Institutes of Health’s Intramural Research Program identified the cytokine, T-cell growth factor, which is now known as interleukin-2 (IL-2). This allowed researchers to better study the immunology of T cells, as well as provided a direct way to ramp up a weak host immune response to cancer. 

Following on from earlier work in the 1950s and 1960s in identifying interferon’s promise in cancer, the first immunotherapy agent that targets interferon-alpha 2 was approved by the US FDA in 1986. Its initial indication was hairy cell leukaemia, but within a decade it was also approved for Stage IIb/III melanoma.

Following the success of cytokine-based immunotherapies and BCG vaccines, scientists began to look even wider for ways to use the immune system against tumours. 

They built upon research in 1987 by Jean-François Brunet where he identified the first immune checkpoint molecule, CTLA-4. However, it wasn’t until 1995 when the University of California, San Francisco’s Dr James Allison suggested that blocking CTLA-4 would enhance the activation of T cell responses in cancer. Next came the discovery of the PD-1 in 1992 by Tasuku Honjo at Kyoto University in Japan. 

Research by Dr Allison in the 1980s had led to better understanding of how T cells work and how they can be used in cancer treatment. However, Memorial Sloane Kettering Cancer Center researchers Michel Sadelain, Renier Brentjens, and Isabelle Rivière took this one step forward by genetically engineering T cells with a chimeric antigen receptor (CAR). 

These so-called CAR-T cells are engineered so they target T lymphocytes to antigens on the surface of tumours, thereby creating a new immunotherapy method.

Bristol Myers Squibb (BMS) became the first company to have a checkpoint inhibitor approved. Yervoy (ipilimumab) is a monoclonal antibody that targets CTLA-4 and turns off the inhibitory mechanism of cytotoxic T lymphocytes, so they can effectively recognise and destroy cancer cells. It was initially approved for melanoma but is now available for colorectal cancer and hepatocellular carcinoma, among others. 

Yervoy was followed in 2015 by Merck and Keytruda (pembrolizumab). Instead of targeting CTLA-4, Keytruda targets another checkpoint, PD-1. Keytruda is now of the world’s most well-known drugs; it has been approved for 17 oncology indications to date. 

These checkpoint inhibitors have significantly extended overall survival in various cancers, compared to standard of care, which is usually chemotherapy.

The use of naturally occurring viruses to treat disease had largely been abandoned in the 1970s, however, researchers began to experiment with using novel technology to engineer viruses to improve their ability to induce an immune response against cancer cells. This therapeutic approach is called oncolytic virus therapy. 

The Herpes Simplex virus type 1 (HSV-1) emerged as an early candidate for cancer immunotherapies. In 2015, the FDA approved BioVex’s T-VEC (talimogene laherparepvec) for melanoma; T-VEC is made from an HSV-1 genetically modified to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). This encouraged the virus to target tumour cells, replicate inside them and induce immunologic responses at the tumour sites. 

To date, this is the only oncolytic virus therapy approved by the FDA, but hundreds of others are in clinical trials for a range of cancers.

A huge medical breakthrough was made in 2017 when Novartis’s CAR-T therapy Kymriah (tisagenlecleucel) was approved by the FDA for patients under 25 with refractory or relapsed B-cell precursor acute lymphoblastic leukaemia. It is a genetically modified, personalised autologous T cell immunotherapy targeted CD19. Since Kymriah has also been approved for diffuse large B-cell lymphoma, a common form of non-Hodgkin lymphoma. 

It was followed one year later by Gilead’s Yescarta (axicabtagene ciloleucel), which similarly targets CD19, but is approved for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Both of these therapies are now widely available globally, including in the UK through the NHS. 

Challenges remain however, as they are only available to certain late-stage blood cancer patients and producing CAR-T therapies for solid tumours still poses problems for researchers. 

In addition, since they are so expensive – more than $400,000 per patient - only a small number of patients who actually have the right cancer type have been treated to date. 

Although checkpoint inhibitors have revolutionised the oncology space, many patients still don’t demonstrate durable long-term responses and are impacted by immune-related adverse events. Checkpoint inhibitors may not be as toxic chemotherapy, but these side effects are still concerning. 

To improve their efficacy and safety in more patients, researchers have started to combine checkpoint inhibitors. This builds on long-standing approaches of combining immunotherapies with chemotherapy. Cancer cells often employ multiple mechanisms to evade the immune system, meaning more than one approach is needed to combat that. 

In 2015, the FDA approved the first combination immunotherapy, Yervoy and BMS’ PD-1 inhibitor, Opdivo (nivolumab) for advanced melanoma. 

Researchers are now looking beyond existing drugs and researching new therapies targeting other checkpoint pathways, which could be combined with the existing drugs. 

A further attempt to improve checkpoint inhibitors involves converting so-called ‘cold’ tumours, which can still evade the immune system, into ‘hot’ ones. Cold tumours are particularly a problem in breast, ovarian, prostate, and pancreatic cancers, leaving these patients ineligible for checkpoint inhibitors. 

Researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have come up with a drug delivery solution; the research was published in Nature Biomedical Engineeringin mid-April. 

Their solution leverages the cytokine IL-12, which is known to turn cold tumours hot, but has serious toxicity issues. Therefore, the research team, led by Jeffrey Hubbell, the Eugene Bell Professor in Tissue Engineering, developed a drug delivery system that attaches IL-2 to a blood protein, which binds to collagen in areas of vascular injury, including in tumours themselves. The IL-12 collagen combination was then used alongside checkpoint inhibitors. 

Delivering IL-12 directly to tumours, reduced its toxicity by two-thirds and researchers saw cancer disappear after treatment in mouse models with aggressive forms of breast cancer. 

The next stage is to study IL-12 in tumours elsewhere in the body, with eventual aim of progressing into clinical trial.