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A novel therapy has been developed by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy and Johns Hopkins Drug Discovery that reprograms immune cells to promote antitumor activity in hard-to-treat prostate and bladder cancers. The study, published in the journal Cancer Immunology Research, focuses on the use of immune-suppressing macrophages, which hinder the immune response to cancers, and reprogramming them into immune-boosting macrophages to enhance therapeutic responses to immunotherapies and other cancer treatments. The researchers hypothesized that blocking immune cells from accessing the amino acid glutamine, which the immune-suppressing macrophages rely on, would shift the balance of macrophages and help shrink tumors.

The experimental glutamine-blocking drug, JHU083, was developed as a prodrug that is converted into an active drug inside the tumor, preventing harmful side effects in the rest of the body. Studies have shown that JHU083 shrinks tumors, reduces cancer spread, and increases survival in animals with various types of cancers, including prostate and bladder cancers. The drug has been shown to reprogram immune-suppressing macrophages into immune-boosting macrophages, triggering tumor cell death and recruiting tumor-killing T-cells and natural killer cells to the tumors. The combination of JHU083 with a checkpoint inhibitor, which boosts T-cell activation in tumors, did not further increase the effects in treated tumors, indicating strong antitumor immune activity already present.

Zarif plans to launch a clinical trial of JHU083 in patients with treatment-resistant prostate or bladder cancer to evaluate its effectiveness in shrinking tumors and preventing metastasis. The researchers also aim to investigate the potential of combining JHU083 with other treatments to further improve its effectiveness against tumors with immune-suppressing macrophages and insufficient T-cells. The study’s findings have implications for improving immunotherapy responses in aggressive forms of prostate and bladder cancers and may offer a promising new treatment option for patients who do not respond to current therapies.

The research team includes co-authors from Johns Hopkins University who have developed and patented technologies related to the findings. Some co-authors have financial interests in Dracen Pharmaceuticals, a company involved in the development of the prodrug JHU083. These relationships are managed in accordance with conflict-of-interest policies at Johns Hopkins University. The study was supported by various grants from the National Institutes of Health and the Maryland Cigarette Restitution Fund, as well as the Bloomberg-Kimmel Institute for Cancer Immunotherapy and the Prostate Cancer Foundation. The innovative approach of reprogramming immune cells to enhance antitumor activity represents a significant advancement in the field of cancer immunotherapy and may lead to more effective treatments for aggressive forms of prostate and bladder cancers.

Overall, the study highlights the potential of reprogramming immune-suppressing macrophages into immune-boosting macrophages to enhance the effectiveness of immunotherapies and other standard-of-care cancer treatments in hard-to-treat cancers. By blocking the use of glutamine in tumors, the experimental drug JHU083 has shown promising results in shrinking tumors, triggering tumor cell death, and recruiting antitumor immune cells. Future clinical trials will further evaluate the effectiveness of JHU083 in patients with treatment-resistant prostate and bladder cancer, with a focus on preventing metastasis and improving overall survival rates. The collaboration between researchers and clinicians at Johns Hopkins University is crucial for translating these findings into new therapies that could benefit cancer patients who have limited treatment options.

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