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’.
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.
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.
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.
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.
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.
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.
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.