For more than a hundred years, scientists have been using pathogens, live or inactivated, injected directly into tumours to kill the cancer, and also finding that this boosted the immune system to deal with other tumours in the body.
The Father of immunotherapy
‘Immunotherapy’ as a cancer treatment began with Dr William Coley of Memorial Sloan Kettering Hospital in New York who used bacterial toxins to fight cancer.
From 1891, for about 40 years, Coley, Head of the Bone Tumour Service at Memorial Sloan Kettering, injected tumours directly with pathogens. The infection prompted a high temperature and a significant immune response, prompting many current scientists to call Coley, ‘the Father of Immunotherapy’ (1).
Coley became famous for his Coley’s Toxins. He actually injected live, highly pathogenic bacteria into inoperable tumours such as osteosarcoma. Salmonella was a favourite pathogen and it is now well-accepted that this pathogen can colonise and eliminate solid tumours.
Coley’s injections were not always made from live bacteria. Coley also used the heat-inactivated Streptococcus pyogenes and Serratia marcescens; and the mixed toxins of Streptococcus erysipelas and the Bacillus prodigiosus (2).
Current immunotherapy drugs perform poorly
For many patients, the idea of having an immunotherapy drug is wonderful news. 'It's going to cure me' is what many believe from the press. These new drugs are supposed to work wonderfully against cancer. But, so far, they haven’t lived up to the hype. One reason for this is that they are not used properly.
Many working oncologists simply see the new immunotherapy drugs, for example the ones that unblock the T-cells (like PD-1 drugs, Pembrolizumab and Nivolumab) simply as new ‘drugs’, often using them immediately following chemo drugs such as Carboplatin and Taxol, and Avastin, or even alongside them. This shows a complete lack of understanding of immunotherapy and the immune system. Furthermore, in the UK unlike the USA, there is still next to no understanding of the gut microbiome and how this is intertwined with the immune system and thus with immunotherapy.
While chemotherapy and radiotherapy try to kill cancer cells, immunotherapy tries to enhance and activate the immune system.
Using chemotherapy and radiotherapy is known to reduce the microbiome and the ability of the immune system to fight cancer - they actually get in the way! And so, using chemo at the same time or just before immunotherapy means the ‘checkpoint inhibitor’ PD-1 drug is far more likely to fail.
Of course the PD-1 immunotherapy drugs are a long way away from Coley’s toxins injected straight into a tumour but in today's world, some scientists use them together.
The idea of using pathogens is still with us
100 years later, BCG (Bacillus Calmette–Guérin), an infectious bacterium related to the one that causes TB, and which has been weakened but is still living, is now commonly used as a vaccine to prevent TB. It is also used with early stage, high grade, non-muscle invasive Bladder cancer. While it is not actually injected into the tumour, the infective agent is held in the bladder for approximately one hour so that it can get to work infecting the cancer (3).It's repurposing infectious pathogens as cancer treatments!
Many vaccines contain inert or safe copies of the real disease. For example, vaccines for rotavirus, yellow fever or influenza have been used by injecting them directly into tumours in mouse models. PD-1 checkpoint inhibitors have been used simultaneously. In humans, research has used papilloma vaccines, a diphtheria vaccine and an attenuated (weaked) polio vaccine. It has been shown that these semi-live vaccines boost the immune system and so help the PD-1 immunotherapy work better (10)
The Salmonella use of William Coley has also not gone away. Researchers from the Department of Experimental Therapeutics of the Beckman Research Institute at the City of Hope Hospital in California produced a review in 2017 entitled, ‘Utilizing Salmonella to treat solid malignancies’ (4). In the review, the researchers highlighted ‘the inherent capacity of Salmonella to colonize and eliminate solid tumors’ with work on pancreatic cancer.
In 2014, a team of scientists injected tumours in dogs, using Clostridium novyi-NT (non-toxic). This bacterium is an obligate anaerobe, i.e. it can only grow in low oxygen conditions. Perfect. A cancer tumour is hypoxic - it has low oxygen.
Three out of 16 patients had tumours that disappeared, three more had theirs 'significantly reduced'. Encouraged, the scientists then treated a 53-year old woman with Leiomyosarcoma; and the treatment worked. It is now well-established that strains of Clostridium bacteria are known for their ability to attack and lyse cancer cells in hypoxic (low oxygen) environments (5).
Filip Janku, who was part of that team, has continued with similar studies at MD Anderson. In January 2021, Janku, along with researchers from more than 10 other cancer centres, completed the first in-human study after eight years of working with animals. In 24 human patients, all with solid cancer tumours that no longer responded to treatment, a single intra-tumoral injection of C. novyi-NT produced germination of the spores and lysis of tumours in 10 patients (6).
In 2019, Columbia University immunologist Nicholas Arpaia produced a strain of non-pathogenic E. coli bacteria that, when injected into mice tumours, ‘tackled the tumour from within, rather like a Trojan horse’. What was remarkable was that this single injection also saw distant tumours regress completely even though they had not been injected (7). The E. coli strains were programmed to self-destruct when they reached a certain number. Arpaia added, "Treatment with engineered bacteria led to priming of tumor-specific T-cells in the tumor that then migrated systemically to also treat distant tumors." The E. coli worked rather like the PD-1 immunotherapy is supposed to work - by unblocking T-cells so that they could do their job.
Several new biotech firms are working on bacteria that can enhance immunotherapy actions. One company, BioMed Valley Discoveries, has been testing injections of the spores of Clostridium novyi-NT in a variety of cancers.
Synlogic is another company looking to use injected bacteria, but this time designed to be a STImulator of INterferon Genes (STING) agonist - they latch on to immune cells that have infiltrated the tumor, and they then activate the STING pathway, resulting in interferon release and tumor-specific T cell responses (8). The researchers talked about ‘up to 87% of patients not responding to checkpoint inhibitors and the need to find ways of helping them work’. They used a non-pathogenic version of E. coli - E. coli Nissel or EcN, saying that it ‘is a versatile platform for the localised modification of the tumour microenvironment’.
Your microbiome protects and corrects
There are many studies which clearly show that certain members of the gut community can cause cancer - pathogens, viruses, parasites and so on. But there is also very clear evidence that the microbiome membership may already attack cancer cells - for example, the 90 plus bacteria that make butyrate, a known cancer cell chemical. Research from the University of North Carolina (9) concluded that ‘These studies demonstrate that microbiota can alter cancer susceptibility and progression by diverse mechanisms, such as modulating inflammation, inducing DNA damage, and producing metabolites involved in oncogenesis or tumor suppression’.
Then there is the use of Fecal Transplants. Already shown to correct C. difficile infections, there is now research going ahead on their use with neurodegenerative diseases like Parkinson’s and Alzheimer’s. Cancer will surely follow.
Early days yet; this has only been studied for 130 years!
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* Helpful Links
Go to: Foods that specifically boost or hinder the microbiome
Go to: Butyrate significantly improves your health
* References
- McCarthy, E.F., 2006. The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop. J., 26: 154-158. PMID: 16789469
- Coley WB. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3:1–48.
- BCG and Bladder cancer; https://www.healthline.com/health/bladder-cancer/bcg-treatment-for-bladder-cancer#procedure
- Ebelt, N.D. and E.R. Manuel, 2017. Utilizing Salmonella to treat solid malignancies. J. Surg. Oncol. DOI: 10.1002/jso.24644
- Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses; Nicholas J Roberts et al, August 2014
- Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors; Clinical Cancer Research, Jan 1; 2021
- Bacteria used as a Trojan Horse - https://www.eurekalert.org/pub_releases/2019-07/cuso-bea062819.php
- Nature Communications; June 1, 2020 Leventhal et al; Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity
- Bhatt, A.P., M.R. Redinbo and S.J. Bultman, 2017. The role of the microbiome in cancer development and therapy. CA Cancer J. Clin. DOI: 10.3322/caac.21398
- Repurposed Infectious pathogen vaccines in cancer treatment