More than three decades ago, the U.S. Food and Drug Administration (FDA) approved Bacillus Calmette-Guérin (BCG) as the first immunotherapy against cancer. And it is still used today to treat early-stage bladder cancer.
Now, a team of researchers from Memorial Sloan Kettering Cancer Center (MSK) and Weill Cornell Medicine is expanding the understanding of how the treatment works — an understanding that could help improve the effectiveness of immunotherapies more broadly.
BCG is a weakened strain of the bacterium Mycobacterium bovis, which is used worldwide as a vaccine against childhood tuberculosis. In the treatment bladder cancer, BCG is used in higher concentrations, and the assumption has long been that it works primarily by infecting local cancer cells thereby drawing the attention of the patient's immune cells to come and attack the tumor — though exactly how it works hasn't been entirely clear. Scientists weren't sure the extent to which the immune response that eliminates the cancer is directed against the bacteria versus the tumor.
"It's an example of a therapy that was proven to be clinically effective before we fully understood all the underlying mechanisms," says physician-scientist Michael Glickman, MD , acting director of the Marie-Josée Kravis Center for Cancer Immunobiology at MSK and a professor of medicine at Weill Cornell Medicine..
In a new study, published May 29 in Cancer Cell , Dr. Glickman and his colleagues showed BCG doesn't just work locally in the bladder, but reprograms and amplifies cells in the bone marrow that give rise to a class of immune cells called myeloid cells — boosting the immune system's ability to fight cancer more generally.
"BCG therapy has been one of the most successful immunotherapies for cancer," adds Steven Josefowicz, PhD , an associate professor of pathology and laboratory medicine at Weill Cornell Medicine and co-senior author of the study, along with Dr. Glickman. "And now it's clear it improves the innate immune system's ability to fight cancer."
The "innate" immune system offers rapid, general defenses against new threats, whereas the "adaptive" immune system prepares responses tailored to threats it has previously encountered.
The research combined a sophisticated analysis of blood samples from bladder cancer patients who had been treated with BCG with studies in mouse models of bladder cancer.
The study was led by co-first authors Andrew Daman, PhD , a postdoctoral researcher in the Josefowicz Lab, and Anthony Antonelli, PhD , a postdoc in the Glickman Lab — who initially conceived of and initiated the project as graduate students in the Weill Cornell Medicine Graduate School of Medical Sciences — as well as Gil Redelman-Sidi, MD , an infectious disease specialist at MSK and member of the Glickman Lab.
Studying BCG's Effects Outside of the Bladder
Scientists have known that BCG, which is injected into the bladder through a catheter, acts locally as an immunotherapy by improving the ability of T cells to eliminate cancer cells. But exactly how this was accomplished wasn't entirely clear.
"Medicine's long understanding has been that in order to work as a treatment, BCG has to be in direct contact with the tumor site," Dr. Daman says. "And you can introduce high concentrations of BCG into the bladder in a way that you can't with other types of cancer, and which doesn't require pumping it throughout the whole body, risking toxic side effects."
The new study maps BCG's broader effects outside the bladder.
Previous research had shown that when given as a vaccine, BCG bacteria raise the body's general defenses against a variety of other infections, including viruses. A recent clinical trial , for example, found the BCG vaccine helped protect nursing home residents against viral respiratory infections.
"So, the question was whether this broader, nonspecific protection that gets stimulated by BCG in the context of infections extends to cancer as well," Dr. Antonelli says. "The scientific understanding had been that BCG was basically confined to the bladder, which is where it was having its effect. But that turns out not to be the full story."
New Insights Into BCG's Anti-Cancer Effects
The team showed that when BCG was administered to mice in their bladders, the bacteria traveled to their bone marrow — and could actually be cultured directly from it.
And it is in the bone marrow, where new immune cells get made, that the bacteria influence the entire body — priming the innate immune system to react to new threats (just as it did for the nursing home residents given BCG vaccinations).
Shifting their attention from mice to bladder cancer patients treated with BCG, the researchers used Progenitor Input Enrichment single cell sequencing (PIE-seq) — a specialized analytical method developed by the Josefowicz Lab — which deeply studies rare circulating hematopoietic stem and progenitor cells from a simple blood draw rather than from a bone marrow sample, the way these cells are typically studied. This approach enabled the researchers to understand how BCG treatment affects stem cells, the early development of immune cells, and the mature myeloid cells that they become.
By comparing gene activity before and after BCG treatment, researchers discovered important changes. The study showed that BCG treatment alters the programming of stem cells and early-stage blood cells in the bone marrow. As a result, new immune cells that develop from these reprogrammed cells become better at fighting tumors.
"These findings show that this training of the innate immune system that happens with the BCG vaccine also happens in the context of bladder administration of BCG to treat cancer," Dr. Redelman-Sidi says.
The study was made possible by the ongoing collection of blood samples from BCG-treated bladder cancer patients by MSK urologic surgeon Eugene Pietzak, MD , who was a co-author of the study. The research also included patients from McGill University.
Combining BCG With Checkpoint Inhibitors
Additionally, the scientists demonstrated in mice that when BCG was combined with another type of immunotherapy called checkpoint inhibitor therapy, it was better at shrinking tumors and extending life than either treatment alone.
Checkpoint inhibitors work by releasing the "brake" on T cells, allowing the body to recognize and attack cancer cells more effectively. These T cells, in turn, take instruction from the myeloid cells that the paper shows BCG stimulates, creating a synergy between the two approaches.
"So, this has broad implications for immunotherapy more generally," Dr. Josefowicz says. "We now know that this reprogramming of immune cells that happens in the bone marrow that enhances innate immunity responses can be a strategy to enhance the effects of existing immunotherapies."
Next steps for the research could explore new ways to stimulate this reprogramming, as well as studying whether introducing BCG into the bladder could boost the effectiveness of immunotherapy against other types of cancer.
"Of course, right now that's quite speculative," Dr. Glickman notes.
BCG: A History of Discovery at MSK
The original studies on BCG were conducted at MSK and launched the modern era of tumor immunology.
In 1959, MSK scientists Lloyd Old, MD, and Donald Clarke, PhD, along with Baruj Benacerraf, MD, of New York University, published a seminal paper in Nature that showed mice injected with BCG developed resistance to implanted tumors. This was the first direct demonstration that the body's immune defenses can be marshaled against cancer. Today, Dr. Old is considered the " father of modern tumor immunology ."
MSK has gone on to play a pioneering role in the development of game-changing immunotherapy treatments including CAR T cell therapy , checkpoint inhibitor therapy , and cancer vaccines . And this year, MSK is launching a new, stand-alone Immuno-Oncology research program to accelerate progress in the emerging field.
"Along with being part of a long history of immunotherapy research at MSK, this is a great example of what we mean when we talk about the power of conducting research at an institution where efforts can move quite seamlessly from the clinic to the lab and back," Dr. Glickman adds.
Additional Authors, Funding, and Disclosures
Additional authors on the study include Lucinda Paddock, Shireen Khayat, Mythili Ketavarapu, Jin Gyu Cheong, Leonardo Jurado, Anna Benjamin, Song Jiang, Dughan Ahimovic, Victoria Lawless, Michael Bale, Oleg Loutochin, Victor McPherson, Maziar Divangahi, Rachel Niec, and Dana Pe'er.
The research was supported by a Department of Defense Horizon Award (CA181350); the National Institutes of Health (5F31HL152706, 5T32CA26029-03, 5T32AI134632, 5T32GM152349, P50CA221745, P30 CA008748, R01AI148416, R01AI148416-S2); the Ludwig Center for Cancer Immunotherapy at MSK; the National Science Foundation (2139291); a Burroughs Wellcome Fund Pathogenesis of Infectious Disease Award; a Hirschl Weill-Caulier Award; a Bochner-Fleisher Research Grant; the Canadian Institute of Health (MM1-174910); a Fonds de Recherche du Québec-Santé Award; the Strauss Chair in Respiratory Diseases; the Royal Society of Canada; and a Fonds de Recherche du Québec-Santé studentship.
Drs. Antonelli, Daman, Glickman, Josefowicz and Redelman-Sidi have submitted a patent related to the work (CRNU-P0029W0). Dr. Glickman reports equity and consulting fees from Vedanta Biosciences and consulting fees from Fimbrion therapeutics. Dr. Josefowicz is a co-founder of Epistemyx, Inc.
Read the study: " Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity ," Cancer Cell. DOI: 10.1016/j.ccell.2025.05.002
