Written by Leanna Bai ‘25
Edited by Josephine Chen ‘24
Cancer is the second most common cause of death in the United States (1). As cancer biologists continue to search for strategies to safely and effectively eliminate tumor cells, research has recently been directed toward the immune system. Manipulating the body’s innate functions to battle cancer is a promising direction, with the 2018 Nobel Prize in Physiology or Medicine honoring the work in this field (2). Following this momentum, researchers in Houston’s MD Anderson Cancer Center have recently published data that illustrates the potential of immune-stimulant antibody conjugates (ISACs) in targeting tumors derived from HER2+ cancers, such as breast, bladder, pancreatic, ovarian, and stomach cancers.
To define ISACs, one may approach it as a hybrid drug: one component is an antibody, and the second component includes immune-stimulating factors. The antibody binds to the tumor cell surface, and the factors activate receptors that amplify the immune response (3). The specific drug studied at MD Anderson is called NJH395: a novel combination of an anti-HER2 antibody and Toll-like receptor 7 activator (the stimulation of this receptor leads to the secretion of cytokines, defined as signaling molecules that intensify antitumor activities) (4). This is a clever conjugation, and the study explores the safety, efficacy, and clinical results of this drug.
The study began by testing NJH395 activity in vitro, confirming that this compound molecule 1) binds to HER2+ tumor cells and 2) induces cytokine release. Then, the researchers tested the drug’s antitumor capacity on human cells grafted onto mice, which also resulted in immune activation (4).
Building on the promising preclinical data, the researchers began a phase one clinical trial: 18 patients with advanced HER2+ tumors received one dose of NJH395 to assess the safety and efficacy of this drug. Of the participants, 17 reported 132 side effects, including the symptoms of cytokine release syndrome: nausea, headache, and vomiting. Due to these safety concerns, the clinical trial did not progress to increase the dosage (4).
Although early results demonstrate the potential of ISACs in combating cancer, further research on adverse effects is necessary — despite its potential for a targeted response against HER2+ tumors, NJH395 also elicited generalized immune activation, which may be dangerous for patients (4). However, with a sample size of only 18 patients, additional studies may provide more insight into the capacity of ISACs as anticancer therapeutics.
Overall, this preliminary study draws attention to the potential of ISACs in combating cancer. This paper demonstrates encouraging preclinical data that serves as “proof-of-mechanism” for this drug and sets the stage for further exploration of NJH395’s reaction on human tumor cells. As researchers turn towards the development of a safer, more effective ISAC, this study provides a glimmer of hope for the use of the immune system as a means of battling cancer.
References
[1] ACS Medical Content and News Staff. Risk of Dying from Cancer Continues to Drop at an Accelerated Pace. American Cancer Society [Internet]. 2022 Jan 12 [cited 2022 Dec 11]. Available from: https://www.cancer.org/latest-news/facts-and-figures-2022.html#:~:text=Cancer%20continues%20to%20be%20the,about%201%2C670%20deaths%20a%20day
[2] The Nobel Prize in Physiology or Medicine 2018 Press Release. The Nobel Prize [Internet]. 2018 Oct 1 [cited 2022 Dec 11]. Available from: https://www.nobelprize.org/prizes/medicine/2018/press-release/
[3] McDermott, Amy. Novel cancer-killing drug type harnesses the immune system. PNAS Journal Club [Internet]. 2022 Nov 18 [cited 2022 Dec 11]. Available from: https://www.pnas.org/post/journal-club/cancer-killing-drug-strategy-harnesses-immune-system
[4] Filip Janku, Sae-Won Han, Toshihiko Doi, Alessio Amatu, Jaffer A. Ajani, Yasutoshi Kuboki, et al. Preclinical Characterization and Phase I Study of an Anti–HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies. Cancer Immunology Research [Internet]. 2022 Dec [cited 2022 Dec 11]. DOI: https://doi.org/10.1158/2326-6066.CIR-21-0722
[Image] Antibody.jpg [Internet] [cited 2022 Dec 11] Available from: https://wis-wander.weizmann.ac.il/life-sciences/antibodies-fight-cancer-too