Thread by @tony_breu

1/16
Why do we use a vaccine (BCG) to treat an unrelated malignancy (bladder cancer)?

Can infections really prevent/treat cancer?

Let's find out.

2/
This story begins in 1813 when Arsène-Hippolyte Vautier reported that patients suffering from gas gangrene experienced a decrease in the size of their malignant tumors.

An explanation (or even the causative bacterium!) wasn't immediately apparent.

pubmed.ncbi.nlm.nih.gov/28202530/

3/
Decades later, Williams Coley heard about the curious case of a man with inoperable sarcoma that disappeared after erysipelas developed.

The remission was durable out to at least 7 years.

dx.doi.org/10.1097/000006…

4/
After hearing about this case, Coley wondered whether intentional injection of Streptococcus pyogenes might work too.

In 1893 he reported tumor regression in several patients with this therapy.

What was going on?

dx.doi.org/10.1097/000006…

5/
In 1929, Raymond Pearl reported another curious finding.

In an autopsy study, he found a lower frequency of cancer in those with evidence of tuberculosis.

[I'll soon post a historical note on the problems with this study.]

doi.org/10.1093/oxford…

6/
Based on the above, researchers began to study Bacillus Calmette-Guerin (BCG). Old et al found that BCG-infected mice showed increased resistance to tumors.

In one experiment, the 48-day mortality was:
😀0% in BCG infected
🙁92% in uninfected controls

pubmed.ncbi.nlm.nih.gov/14428599/

7/
The first trial of BCG in humans wasn't actually for bladder cancer. Instead, it was for acute lymphoblastic leukemia (ALL).

30 patients with ALL in remission after chemo were treated. Relapse rates were:

😐63% in BCG treated
🙁100% in controls

pubmed.ncbi.nlm.nih.gov/4182654/

8/
Although many tumor types appeared to respond to BCG, bladder cancer emerged as the perfect option for this therapy.

Why?

Injecting the attenuated bacteria in the bladder allowed for a more controlled introduction to tumor cells.

pubmed.ncbi.nlm.nih.gov/17997439/

9/
The promise of BCG therapy in bladder cancer became clear with the results of a small trial by Morales et al.

They treated 9 patients with recurrent non-muscle invasive bladder cancer with BCG and found a 12-fold reduction in recurrence.

pubmed.ncbi.nlm.nih.gov/820877/

10/
In subsequent years, BCG has also been compared head-to-head against chemotherapy and proved superior.

The probability of disease-free survival at five years:
😐45% in BCG treated
🙁18% in doxorubicin treated

pubmed.ncbi.nlm.nih.gov/1922207/

11/
Overall, meta-analyses have demonstrated the following odds ratios for tumor recurrence:

☞ 0.61 (compared with control)
☞ 0.56 (compared to mitomycin C)

pubmed.ncbi.nlm.nih.gov/16765182/
pubmed.ncbi.nlm.nih.gov/15947584/

12/
What is BCG doing to cause this anti-tumor effect? The short answer, it is:

💥Immunotherapy💥

BCG activates nearly all aspects of the immune system, including both innate and adaptive.

pubmed.ncbi.nlm.nih.gov/24492433/

13/
While we often equate the immune system with our fight against infectious diseases, it also has a key role in tumor recognition and rejection.

The emergence of checkpoint inhibitors demonstrates well the power of immunotherapy.

pubmed.ncbi.nlm.nih.gov/28783669/

14/
Another mechanism of benefit with BCG may be Trained Immunity.

This is the concept that innate immune cells (e.g., macrophages) "trained" by one infection (or vaccine) respond with a heightened response to a second, unrelated, infection.

pubmed.ncbi.nlm.nih.gov/34131332/

15/
Before closing, it's worth mentioning another way immune activation by BCG can benefit.

Reduction in non-TB infections.

For example, a recent RCT reported a decrease in new infections after BCG vaccination:
🙁42% for placebo
🙂25% for BCG

pubmed.ncbi.nlm.nih.gov/32941801/

16/16 - SUMMARY
⚡️For centuries bacterial infections have been observed to reduce tumor size
⚡️These observations led to trials of BCG for cancer, including bladder cancer
⚡️BCG acts as a form of immunotherapy, leading to immune destruction of cancer cells