Medical Bulletin 02/ December/ 2024 - Video

A multinational collaboration co-led by the Garvan Institute of Medical Research has uncovered a potential explanation for why some cancer patients receiving a type of immunotherapy called checkpoint inhibitors experience increased susceptibility to common infections.

The findings, published in the journal Immunity, provide new insights into immune responses and reveal a potential approach to preventing the common cancer therapy side effect.

"Immune checkpoint inhibitor therapies have revolutionised cancer treatment by allowing T cells to attack tumours and cancer cells more effectively. But this hasn't been without side effects -- one of which is that approximately 20% of cancer patients undergoing checkpoint inhibitor treatment experience an increased incidence of infections, a phenomenon that was previously poorly understood," says Professor Stuart Tangye, co-senior author of the study and Head of the Immunology and Immunodeficiency Lab at Garvan.

"Our findings indicate that while checkpoint inhibitors boost anti-cancer immunity, they can also handicap B cells, which are the cells of the immune system that produce antibodies to protect against common infections. This understanding is a critical first step in understanding and reducing the side effects of this cancer treatment on immunity."

The researchers focused on the molecule PD-1, which acts as a 'handbrake' on the immune system, preventing overactivation of T cells. Checkpoint inhibitor therapies work by releasing this molecular 'handbrake' to enhance the immune system's ability to fight cancer.

The study, which was conducted in collaboration with Rockefeller University in the USA and Kyoto University Graduate School of Medicine in Japan, examined the immune cells of patients with rare cases of genetic deficiency of PD-1, or its binding partner PD-L1, as well as animal models lacking PD-1 signalling. The researchers found that impaired or absent PD-1 activity can significantly reduce the diversity and quality of antibodies produced by memory B cells, i.e. the long-lived immune cells that 'remember' past infections.

Reference: https://www.garvan.org.au/news-resources/news/study-reveals-cause-of-common-cancer-immunotherapy-side-effect

For pregnant women, exposure to fine particulate air pollution (PM2.5) was associated with altered immune responses that can lead to adverse birth outcomes, according to a new study led by Harvard T.H. Chan School of Public Health. The study was published in Science Advances.

Key points from the study are:

Exposure to PM2.5 was associated with higher levels of inflammation among pregnant women, potentially leading to adverse birth outcomes.

Study examined PM2.5 and maternal and fetal health on a single-cell level, using an innovative technology to detect how pollution modified the DNA within individual cells.

Findings provide new understanding of the biological pathways through which air pollution affects pregnancy and birth outcomes, and further highlight the importance of policy and clinical interventions to limit air pollution exposure for pregnant women.

“This study represents a substantial step forward in understanding the biological pathways through which PM2.5 exposure affects pregnancy, maternal health, and fetal development. Its advanced methodology represents a significant innovation for how we study immune responses to environmental exposures,” said corresponding author Kari Nadeau, John Rock Professor of Climate and Population Studies and chair of the Department of Environmental Health.

To understand the associations on a cellular level, the researchers used air quality data collected by the Environmental Protection Agency to calculate study participants’ average PM2.5 exposure. Participants were both non-pregnant women and 20-week pregnant women. The researchers then used an innovative technology to understand how pollution modified the DNA of participants’ individual cells. Within each cell they were able to map changes to histones, the proteins that help control the release of cytokines—proteins that help control inflammation in the body and that can affect pregnancy.

The study found that PM2.5 exposure can influence the histone profiles of pregnant women, disrupting the normal balance of cytokine genes and leading to increased inflammation in both women and fetuses. In pregnant women, this increase in inflammation can correspond with adverse pregnancy outcomes.

Reference: Youn Soo Jung et al., Impact of air pollution exposure on cytokines and histone modification profiles at single-cell levels during pregnancy.Sci. Adv.10,eadp5227(2024).DOI:10.1126/sciadv.adp5227

Results from a recent Gilead-funded clinical trial (Purpose-2) led by physicians at Emory University and Grady Health System indicate that a twice-yearly injection of Lenacapavir offers a 96% reduced risk of infection overall, making the injection significantly more effective than the daily oral pre-exposure prophylaxis. The findings were published in the New England Journal of Medicine.

In the randomized, double-blind, Phase III clinical trial comparing the efficacy of the two medications, 99% of the participants in the Lenacapavir group did not acquire an HIV infection. During the trial, only two participants in the Lenacapavir group, comprised of 2,179 people, acquired HIV. This compares to nine new HIV infections in the Truvada group, which had 1,086 people. The trial showed that adherence to the injectable was higher than of the daily oral pill.

The inclusion of racially, ethnically, and gender-diverse participants in the clinical trial was notable because it was representative of populations disproportionately impacted by HIV in real time. According to the study, the same populations that are disproportionately impacted by HIV are the same populations that have limited access to pre-exposure prophylaxis -- or may have difficulty consistently taking the oral antiretroviral medication -- ultimately highlighting the need for more options.

Reference: https://news.emory.edu/stories/2024/11/hs_lenacapavir_trial_27-11-2024/story.html