Clinical trials of antitumor vaccination with an autologous tumor cell vaccine modified by virus infection: improvement of patient survival based on improved antitumor immune memory

Abstract

For active specific immunotherapy of cancer patients, we designed the autologous virus-modified tumor cell vaccine ATV-NDV. The rationale of this vaccine is to link multiple tumor-associated antigens (TAAs) from individual patient-derived tumor cells with multiple danger signals (DS) derived from virus infection (dsRNA, HN, IFN-alpha). This allows activation of multiple innate immune responses (monocytes, dendritic cells, and NK cells) as well as adaptive immune responses (CD4 and CD8 memory T cells). Preexisting antitumor memory T cells from cancer patients could be activated by antitumor vaccination with ATV-NDV as seen by augmentation of antitumor memory delayed-type hypersensitivity (DTH) responses. In a variety of phase II vaccination studies, an optimal formulation of this vaccine could improve long-term survival beyond what is seen in conventional standard therapies. A new concept is presented which proposes that a certain threshold of antitumor immune memory plays an important role (1) in the control of residual tumor cells which remain after most therapies and (2) for long-term survival of treated cancer patients. This immune memory is T-cell based and most likely maintained by persisting TAAs from residual dormant tumor cells. Such immune memory was prominent in the bone marrow in animal tumor models as well as in cancer patients. Immunization with a tumor vaccine in which individual TAAs are combined with DS from virus infection appears to have a positive effect on antitumor immune memory and on patient survival.

Fig. 1

The immunological consequences of tumor cell infection by NDV. a The tumor vaccine ATV-NDV is produced by coincubation of 10⁷ 200-Gy irradiated tumor cells with 32 HU of NDV Ulster for 1 h at 37°C. b After intradermal application of the vaccine, virus replication occurs in situ and leads within 24–48 h in the skin to delayed-type hypersensitivity (DTH) reactivity. This may involve distinct innate (4–6) and adaptive (1–3) immune mechanisms as analyzed in vitro.

Fig. 2

Survival curves of vaccinated patients. Primary operated breast cancer patients received postoperative vaccinations with the autologous virus-modified tumor vaccine ATV-NDV in two different formulations given to two cohorts of more than 30 patients with similar risk factors [37]. The figure shows the Kaplan-Meier estimates after a prolonged median observation period of 5.2 years for long-term survival (a) and recurrence-free survival (b). The analysis was performed by FOCUS (Düsseldorf) with the financial support of the Dietmar Hopp-Stiftung (Walldorf). There was a highly significant long-term survival benefit and also a significant benefit in recurrence-free survival in the group which received a vaccine formulation of >1.5×10⁶ viable tumor cells with at least 33% overall cell viability. There were only 5 patients dead in this group as compared to 16 in the other group, which could only receive a suboptimal vaccine formulation. The survival in the latter group corresponds to expectation of patients with similar risk factors under standard therapy without vaccination.