Immunotherapy: building the fourth pillar of cancer treatment

Cancer treatment has been traditionally characterised by surgery, chemotherapy, and radiation. However, in the late 20th century, a fourth element entered the mainstream: immunotherapies.

To appreciate and understand the promising future of immunotherapy in cancer treatment, it is important to reflect on the ground-breaking research and innovations that have paved the way for new cancer treatments over the past century. Here, we chart the remarkable history of immunotherapies and ongoing efforts to make them even more effective.



Fehleisen and Busch explore immune system modulation in cancer

The first scientific attempt to harness immune system modulation to combat cancer appeared in the 19th century after German physicians F Fehleisen and W Busch independently identified a link between accidental erysipelas infections in cancer patients and subsequent spontaneous tumour regression.

Building upon this hypothesis, both physicians sought to confirm this connection by intentionally injecting the erysipelas-causing Streptococcus bacteria into the tumours of several cancer patients. Following the infection, Fehleisen reported tumour shrinkage in three of the seven trial participants, indicating that the immune system had a modulatory role in treating cancer.


William Coley develops first immunotherapy

The earliest case of cancer immunotherapy can be traced back to the late 1800s, when the New York bone surgeon and subsequent ‘father of immunology’ William Coley first attempted to leverage the immune system to treat cancer.

Similar to Fehleisen and Busch, Coley also observed similar patterns between acute bacterial infection and spontaneous tumour regression. Using this insight, he instigated a 40-year study, during which more than 1,000 cancer patients were injected with mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens bacteria, later known as ‘Coley’s toxins’.



Early indications of CAR-T emerge

Although CAR-T therapy (see below) has substantially developed over the past few decades, an early example of the treatment appeared in the work of Dr Ferdinand Blumenthal and Dr E. von Leyden. In 1902, the duo attempted to treat patients using suspension derived from their own autologous tumour tissue culture. However, while some improvement was noted, the study did not result in significant tumour regression.


Ehrlich’s magic bullet theory

The achievements and contributions of the Nobel prize-winning German scientist Paul Ehrlich are well documented throughout the history of immunology. But in 1907, he put forward a hypothesis for a so-called ‘magic bullet’ of synthesised antibacterials designed to impact specific targets in the body. This initial idea formed the foundation for key cancer and immunotherapy developments, including chemoreceptor and chemotherapy concepts over the following century.


Discovery of tumour-associated antigens

The 1940s were a turbulent period for immunotherapy research. Amid hesitancy in the medical community regarding the use of the treatment, fuelled by a general lack of understanding of the mechanism of action, newly approved chemotherapies began to gain prominence alongside the traditional surgical treatment approach.

However, despite this hesitancy, researchers used Ehrlich’s early research into antibodies and antigens as a foundation for studies conducted on tumours derived from animal subjects. From these studies emerged a significant discovery: “tumour-associated antigens” (TAAs), which the immune system could potentially recognise.

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.



Discovery of interferon

While there is debate over who should be credited for the discovery of interferon – a cytokine produced by white blood cells – it is commonly accepted that the proteins were first identified by Scottish virologist Alick Isaacs and Swiss virologist Jean Lindenmann.

It was initially considered for use as a general anti-viral, however, subsequent research found interferon to be highly effective as an anti-cancer therapy in mice models.


First example of a cancer vaccine emerges

In the late 50s, the husband-and-wife team of Ruth and John Graham unveiled results from the first-ever cancer vaccine trial. The research included 114 patients with gynaecological cancers who were treated with an adjuvanted tumour lysate.

Although results showed a 22% incidence of remission or stable disease, the research received little attention from the medical community.


Miller confirms existence of T cells

At just 30 years old, French-Australian immunologist Jacques Miller made a ground-breaking discovery, becoming the last person to identify the function of a human organ – the thymus. Then, just seven years later, he made an equally impressive discovery when he uncovered the presence of T cells and their role in mediating the immune response.


Researchers unlock the promise of interleukins

While attempting to grow T cells in a culture, Researchers from the US National Institutes of Health’s Intramural Research Program, led by renowned biomedical researcher Robert Gallo, identified the cytokine T cell growth factor, now known as interleukin-2 (IL-2). This broadened researchers’ understanding of the immunology of T cells and revealed a direct way for oncologists to boost the patient’s immune response to cancer.


FDA approves first immunotherapy agent

Building upon the promise of interferon in oncology treatment, immunology achieved a significant milestone in 1986, when the first immunotherapy agent, an antitumor cytokine called interferon-alpha 2 (IFN-a2), was approved by the US Food and Drug Administration (FDA). Initially indicated for hairy cell leukaemia, the treatment was later green-lit for Stage IIb/III melanoma treatment.


Rise of checkpoint inhibitors

Following the success of cytokine-based immunotherapies, scientists continued to seek other areas where the immune system could be leveraged against tumours. With the discovery of the PD-1 as an inducible gene on activated T-lymphocytes in 1992, Tasuku Honjo at Kyoto University in Japan made a significant contribution to the development of future PD-1/PD-L1 blocking therapies.

Drawing upon Jean-François Brunet’s research of the first immune checkpoint molecule, CTLA-4, in 1897, a study led by Dr James Allison at the University of California, San Francisco, sought to clarify the ambiguities of the molecule’s function. Through this study, Allison and his team pinpointed CTLA-4 as a critical immune checkpoint molecule that held strong potential as a future anti-cancer therapy target.



Birth of CAR-T therapy

Although Dr Allison’s research into the function and application of T cells in cancer treatment had greatly broadened the scientific understanding of the immune system. However, in 2002, Memorial Sloane Kettering Cancer Center scientists Michel Sadelain, Renier Brentjens, and Isabelle Rivière opted to push the boundaries of the T cell research even further by genetically engineering T cells with a chimeric antigen receptor (CAR).

This new approach paved the way for a new generation of immunotherapy treatments. Dubbed CAR-T therapy, these modified cells are programmed to help T cells attach to a specific cancer cell antigen on the surface of tumours.



First checkpoint inhibitor approved

In March 2011, Bristol Myers Squibb (BMS) made headlines as the first company to be granted market approval for its checkpoint inhibitor Yervoy (ipilimumab).

Yevory is a monoclonal antibody designed to activate the immune system by targeting CTLA-4 and disrupting the inhibitory mechanism that prevents T lymphocytes from identifying and destroying cancer cells. The FDA initially approved the therapy for melanoma indications; however, Yevory has since been granted approval for multiple designations by regulators around the world.


FDA makes history with first CAR-T therapy approval 

CAR-T therapy achieved a major milestone in late 2017 when Novartis’s Kymriah (tisagenlecleucel) became the first gene therapy to receive FDA approval. The action ushered in a new approach to cancer treatment, using genetically modified autologous T cell immunotherapy to target and kill the cancer cells.

Initially designated for patients under 25 with refractory or relapsed B-cell precursor acute lymphoblastic leukaemia, the treatment has now been authorised for diffuse large B-cell lymphoma, a common form of non-Hodgkin lymphoma.

A few months later, Gilead’s Yescarta (axicabtagene ciloleucel) became the second cell-based gene therapy approved by the FDA as a treatment for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.


Researchers receive Nobel prize for checkpoint inhibitors

The importance of cancer immunotherapy was underlined in 2018 when James Allison and Tasuku Honjo were granted the Nobel Prize for their early work on CTLA4 and PD-1 checkpoint inhibitors, respectively.


Enhertu scores first FDA approval 

AstraZeneca/Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) scored accelerated approval from the FDA to treat HER2-positive metastatic breast cancer after at least two prior therapies in late 2019. Since then, the antibody-drug conjugate has been cleared for use in approximately 40 countries.


Killer innate-like T cells identified as ‘soldier’ for cancer therapy 

Six years after the discovery of what scientists have dubbed ‘killer innate-like T cells’, researchers at the Sloan Kettering Institute in New York published a report in Nature, which identified that the immune cell ‘soldier’ could be a good target for immunotherapy, raising hopes that it might help narrow the gap between people who respond and those who do not.

About the author

Eloise McLennan is the editor for pharmaphorum’s Deep Dive magazine. She has been a journalist and editor in the healthcare field for more than five years and has worked at several leading publications in the UK.

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