A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

Abstract

Purpose: A Phase 2 trial of stereotactic radiation therapy and in situ cytotoxic virus therapy in metastatic triple-negative breast cancer (mTNBC) patients followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mTNBC patients. Methods: In this single-arm, open-label Phase 2 trial, mTNBC patients were treated with ADV/HSV-tk (5 x 1011 vp) intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200mg, Q3w). The primary endpoint was clinical benefit rate (CBR, CR, PR or SD≥ 24 weeks per RECIST version1.1 at non-irradiated site). Secondary endpoints included duration on treatment (DoT), OS and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: 28 patients were enrolled and treated. CBR was seen in 6 patients (21.4%) including two CR (7.1%), one PR (3.6%) and three SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with CyTOF and IMC revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated mTNBC patients. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Breast Cancer: An Overview of Current Therapeutic Strategies, Challenge, and Perspectives

“… 90 Another phase 2 trial includes 28 patients with metastatic TNBC to explore the value of in situ virus gene therapy (ADV/HSV-tk) plus stereotactic body radiotherapy and pembrolizumab, and the result demonstrated that clinical benefit rate was 21.4%, and patients with clinical benefit had durable responses, with improved median duration on treatment (9.6 months) and OS (14.7 months). 91 Use of microRNA in anti-cancer therapy also showed promising results in inhibiting breast cancer cell proliferation and development. MRX34, to our knowledge, is one of the first miRNA replacement agents (miR-34a), and now in entering clinical trials.…”

The Biocatalysis in Cancer Therapy

“…Valacyclovir (VACV) could be rapidly converted to acyclovir by valacyclovirase (VACVase), a serine hydrolase in the liver (Figure B) . The cascade phosphorylation of acyclovir to a toxic form could then be performed by adenovirus-mediated expression of HSV-TK and CKs (Figure B). , Rabacfosadine (GS-9219, 112 ) is a prodrug of the acyclic nucleotide analogue 9-(2-phosphonylmethoxyethyl)­guanine (PMEG, 114 ) that was approved for the treatment of canine lymphoma. Rabacfosadine is first converted by cathepsin A to N6-cyclopropyl-9-(2-phosphonylmethoxyethyl)­diaminopurine (cpr-PMEDAP, 113 ) and then by aminohydrolase to PMEG.…”

Nanobiotechnology‐mediated radioimmunotherapy treatment for triple‐negative breast cancer

“…73 Since immunotherapy alters the balance between immunity and immune tolerance, the increased likelihood of tumor recognition is accompanied by a higher immune response rate in normal tissues. In a Phase 2 trial of radioimmunotherapy for metastatic TNBC, 95 28 patients were enrolled and treated. Clinical benefit rate was seen in six patients (21.4%), and the median overall survival increased by more than 2-fold in patients with clinical benefit.…”