Insights into Bladder Cancer Treatment for Immunotherapies

More than three decades ago, the U.S. Food and Drug Administration (FDA) approved Bacillus Calmette-Guérin (BCG) as the first immunotherapy against cancer.

A team of researchers from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSK) 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 and in the treatment of bladder cancer.

In a study published in May in Cancer Cell, co-senior authors Dr. Steven Josefowicz and Dr. Michael Glickman 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.

The study was led by co-first authors Dr. Andrew Daman, a postdoctoral researcher in the Josefowicz Lab, and Dr. Anthony Antonelli, 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 Dr. Gil Redelman-Sidi, an infectious disease specialist at MSK and member of the Glickman Lab.

The new study maps BCG’s broader effects outside the bladder.

In examining patients with bladder cancer who were treated with BCG using Progenitor Input Enrichment single-cell sequencing (PIE-seq) — a specialized analytical method developed by the Josefowicz Lab that deeply studies rare circulating hematopoietic stem and progenitor cells from a simple blood draw rather than from a bone marrow sample — the researchers were able 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 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.

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.

“BCG therapy has been one of the most successful immunotherapies for cancer,” says Dr. Josefowicz. “And now it’s clear it improves the innate immune system’s ability to fight cancer.”

A previous version of this story ran in the Weill Cornell Medicine online newsroom.