1. ¹The Institute of Cancer Research, Cancer Research UK Center for Cell and Molecular Biology, London, UK
2. ²Drug Development Unit, The Royal Marsden Hospital NHS Foundation Trust, London and Sutton, UK
3. ³Oncolytics Biotech Inc., Calgary, Canada
4. ⁴Postgraduate Medical School, University of Surrey, Guildford, UK
5. ⁵Leeds Institute of Molecular Medicine, St James's University Hospital, University of Leeds, Leeds, UK
6. ⁶Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA

Correspondence: Dr KJ Harrington, The Institute of Cancer Research, Cancer Research UK Center for Cell and Molecular Biology, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK. E-mail: kevinh@icr.ac.uk

⁷Joint senior authors.

Received 23 September 2007; Revised 21 December 2007; Accepted 23 December 2007; Published online 6 March 2008.

Abstract

There is an emerging realization from animal models that the immune response may have both detrimental and beneficial therapeutic effects during cancer virotherapy. However, there is a dearth of clinical data on the immune response to viral agents in patients. During a recently completed phase I trial of intravenous reovirus type 3 Dearing (RT3D), heavily pretreated patients with advanced cancers received RT3D at doses escalating from 1 10⁸ tissue culture infectious dose-50 (TCID₅₀) on day 1 to 3 10¹⁰ TCID₅₀ on 5 consecutive days of a 4 weekly cycle. A detailed analysis of the immune effects was conducted by collecting serial clinical samples for analysis of neutralizing anti-reoviral antibodies (NARA), peripheral blood mononuclear cells (PBMC) and cytokines. Significant increases in NARA were seen with peak endpoint titres >1/10 000 in all but one patient. The median fold increase was 250, with a range of 9–6437. PBMC subset analysis showed marked heterogeneity. At baseline, CD3+CD4+ T cells were reduced in most patients, but after RT3D therapy their numbers increased in 47.6% of patients. In contrast, most patients had high baseline CD3+CD8+ T-cell levels, with 33% showing incremental increases after therapy. In some patients, there was increased cytotoxic T-cell activation post-therapy, as shown by increased CD8+perforin/granzyme+ T-cell numbers. Most patients had high numbers of circulating CD3- CD56+ NK cells before therapy and in 28.6% this increased with treatment. Regulatory (CD3+CD4+CD25+) T cells were largely unaffected by the therapy. Combined Th1 and Th2 cytokine expression increased in 38% of patients. These data confirm that even heavily pretreated patients are capable of mounting dynamic immune responses during treatment with RT3D, although these responses are not clearly related to the administered virus dose. These data will provide the basis for future studies aiming to modulate the immune response during virotherapy.