Effect of Modified Vaccinia Ankara–5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer

Abstract

isrctn.org Identifier: ISRCTN54669986.

T‐cell modulation by cyclophosphamide for tumour therapy

“…The differential effect could be due to the use of CY in patients with earlier stage cancers and hence lower tumour burdens; baseline frequencies of Treg cells in this patient group, although greater than healthy controls, was statistically lower than in patients with late‐stage melanoma, a finding also observed in colorectal cancer . A recent randomized controlled phase I/II study performed by our group administered low‐dose CY with or without a modified vaccinia Ankara‐based vaccine encoding the oncofetal antigen 5T4 (TroVax) to stage IV colorectal cancer patients, a notoriously poorly responsive tumour to immunotherapy . Compared with no treatment control patients, Treg cell depletion was observed in 24/27 (89%) patients receiving 50 mg CY twice a day, although unlike previous reports, significant B‐cell and natural killer cell depletion was also detected.…”

“…Compared with no treatment control patients, Treg cell depletion was observed in 24/27 (89%) patients receiving 50 mg CY twice a day, although unlike previous reports, significant B‐cell and natural killer cell depletion was also detected. Notably, significant increases in the frequency and magnitude of 5T4‐specific interferon‐ γ + and granzyme B + T‐cell responses were observed, but not for control antigens; these were associated with a significant increase in progression‐free survival . Unexpectedly, although TroVax also induced beneficial anti‐5T4 cellular and humoral responses to the benefit of patient progression‐free and overall survival, there was no synergistic effect of combining CY with vaccine in terms of boosting observed anti‐5T4 immunological responses or patient survival .…”

“…Notably, significant increases in the frequency and magnitude of 5T4-specific interferon-c + and granzyme B + T-cell responses were observed, but not for control antigens; these were associated with a significant increase in progression-free survival. 71,72 Unexpectedly, although Tro-Vax also induced beneficial anti-5T4 cellular and humoral responses to the benefit of patient progressionfree and overall survival, there was no synergistic effect of combining CY with vaccine in terms of boosting observed anti-5T4 immunological responses or patient survival. 71 This warrants further, larger-scale trials of CY and vaccination strategies in colorectal cancer, possibly with different treatment timings.…”

The opposing roles of CD4+ T cells in anti‐tumour immunity

“…In agreement with limiting innate stimuli, CTL responses against cancer often rely on the provision of CD4 + T‐cell help . Moreover, effective therapeutic vaccination strategies against cancer have been recently shown to induce potent anti‐tumour CD4 + T‐cell responses directed against mutated or non‐mutated cancer antigens …”

A Retrospective Exploration of Targeted Maintenance Therapy in Advanced Colorectal Cancer: Based on the Background of Chinese Patient Assistance Program

“…Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of death from cancer worldwide (1). The prognosis of patients with CRC is poor (2,3); that is, more than half of patients will ultimately develop metastases (4)(5)(6). The median overall survival (OS) in patients with mCRC is ∼30 months (7) due to the availability of several chemotherapy drugs and targeted drugs as well as the development and popularization of multidisciplinary treatment models (8)(9)(10).…”