Immunological Effects of Low-dose Cyclophosphamide in Cancer Patients Treated With Oncolytic Adenovirus

Abstract

Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T(regs)) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.

Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8+T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer

“…We think that oral low-dose CPO potentially worked together with ONCOS-102 to reduce tumor-induced immune tolerance. 19,20 Such a therapy-induced change to the microenvironment could make tumors susceptible to other immunotherapies.…”

“…Since regulatory cells are known to contribute to the tolerogenic microenvironment that compromises antitumor immune responses, 3,4,18 concomitant low-dose (50 mg daily) cyclophosphamide was included to downregulate tumor-promoting T regulatory cells. 19,20 This chemoimmunomodulation was given orally, starting 1 day after the first virus injection and continuing up until day 169.…”

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

“…[10][11][12] Similarly, administration of cyclophosphamide, at a dose substantially lower than the maximum tolerated dose (MTD) (metronomic dosing), 13 has next to its direct antitumor activity several effects on the bone marrow microenvironment, including immune stimulatory activity. [14][15][16][17][18][19][20][21][22] We hypothesized that the addition of low-dose metronomic oral cyclophosphamide to lenalidomide may be an attractive strategy for lenalidomide-refractory MM patients. Indeed, we previously showed in a small retrospective study that lenalidomide (Revlimid) combined with continuous low-dose oral cyclophosphamide (Endoxan) and prednisone (REP) has remarkable activity in heavily pretreated, lenalidomide-refractory MM patients.…”

Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer

“…Importantly, also oncolytic adenoviruses skew the adaptive immunity toward Th1 phenotype, both preclinically and in cancer patients (17,50), which suggests further combinatorial benefits with trastuzumab. Finally, both activated NK cells and oncolytic viruses can augment antigen processing of DCs by lysing tumor cells and spreading tumor epitopes (14,36).…”