Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases. Compared with other types of breast cancer, TNBC is more likely to spread, metastasize, and recur, and as it lacks therapeutic targets, patients face a poor prognosis in most cases, which has been an obstacle to finding effective treatment.
Patients with TNBC lack the expression of three therapeutic targets, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). Currently, the standard of care for early-stage TNBC is chemotherapy and Panitumumab, but these therapies have significant side effects. Many studies have shown that patients with higher levels of immune cells within the tumor tend to respond better to treatment. This suggests that drugs that stimulate the immune system may be beneficial.
Oncolytic viruses (OVs) are one promising treatment for solid tumors. When injected directly into the tumor, these viruses target cancer cells without affecting normal cells, causing them to lyse by replicating inside the cancer cells; besides, they can further trigger a systemic immune response to kill cancer cells.
On February 9, 2023, researchers at Moffitt Cancer Center in the United States published a paper in Nature Medicine, a leading international medical journal, entitled “Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial”. In this phase 2 trial, 37 patients with TNBC received standard chemotherapy combined with Talimogene laherparepvec (T-VEC) prior to surgery. Residual tumor burden (RCB) was used to assess treatment efficacy after treatment. 45.9% of patients (17/37) achieved complete remission after treatment, and 89% of patients (33/37) had no disease recurrence within two years after treatment.
T-VEC, a modified herpes simplex virus type 1 (HSV-1)-based OV therapy developed by Amgen, was approved by the Food and Drug Administration (FDA) in 2015 for the treatment of advanced melanoma. It is the first OV therapy approved by the FDA.
T-VEC contains sequences encoding GM-CSF proteins that stimulate the immune system, and when injected into tumors, it replicates and expresses GM-CSF proteins within tumor cells, causing tumor cell lysis and releasing tumor-derived antigens and GM-CSF proteins to accelerate the anti-tumor immune response.
In this clinical trial, the team evaluated the efficacy of a combination of T-VEC and standard chemotherapy given prior to surgery in patients with TNBC. In 37 patients, 45.9% achieved disease remission, and 89% were free of recurrence within two years of treatment. The safety of the combination therapy did not differ significantly from that of standard chemotherapy, except for higher levels of low-grade fever, chills, headache, and pain in the injection site.
The team also analyzed immune biomarker levels and assessed whether these biomarkers correlated with patient response. They found that the majority of tumor samples had higher levels of activation of anti-tumor T cells and immune signaling pathways during the first 6 weeks of treatment. Patients who responded better to treatment had higher levels of CD8 T cells at week 6 than those who did not respond to treatment. These observations suggest that early activation of the immune response may lead to better outcomes for patients with TNBC.
Professor Hatem Soliman, leader of the clinical trial, said these results suggest that T-VEC combined with standard chemotherapy may increase response in patients with high-risk, early-stage TNBC. There is evidence of strong immune activation within the tumor, and T-VEC combined with current chemoimmunotherapy is warranted for the treatment of TNBC.
Reference
1. Lareau, Caleb A., et al. “Latent human herpesvirus 6 is reactivated in CAR T cells.” Nature 623.7987 (2023): 608-615.