Tumor Antigens And Cancer Vaccines

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Prior to the identification of specific TSA and TAA sequences, tumor antigens were provided from tumor cells, either as lysates or as irradiated cell lines derived from either autologous or allogeneic tumors. The perception is that good anecdotal and phase I/II studies have never translated into positive randomized trials. However, there are two positive randomized vaccine trials, one for colorectal cancer and the other for renal, both published in the Lancet (Jocham et al., 2004; Vermorken et al., 1999).

Vaccines made from autologous tissue are "procedure" vaccines as opposed to "product" vaccines. An alternative to autologous vaccines is the use of established allogeneic cell lines which express shared antigens. Concerns about HLA matching do not appear to be a negative concern as preclinical models show that allogeneic cell lines are often better than autologous— presumably because "allo" represents a danger signal and is more likely to break tolerance.

There are several allogeneic cell line-based vaccines. The most advanced is the triple melanoma cell line vaccine of Donald Morton of the John Wayne Cancer Institute, Santa Monica (Faries and Morton, 2005; Morton et al., 2002). Single institution results in phase II show a clear survival benefit but in a multicenter randomized study the Data Monitoring Committee recommended halting the stage IV trial due to similarity of both treatment and the control arm. The stage III results are not known at the time of writing.

Prostate cancer has provided an ideal candidate for cancer vaccines with a superb surrogate marker in prostate specific antigen (PSA) levels and an absence of effective nontoxic treatment after hormone failure. At least three candidates use cells as the basis of the vaccine, Dendreon uses the patients own DCs pulsed with a prostate alkaline phosphatase-based antigen. In a randomized study, patients on the vaccine arm had a 20% improval in mean survival. Cellgenesys are using two allogeneic cell lines transfected with GM-CSF as a vaccine, with no published results at time of writing. Onyvax have used three allogeneic cell lines which have been enhanced for antigenicity and immunogenicity without using gene transfer technologies. A 42% response of prolonged production in the rate of rise of PSA has been reported in a hormonally refractory study where mean time to progression was 58 weeks (Michael et al., 2005). Therion, using a viral vector-based delivery system using PSA as the antigen, has also claimed efficacy, and a recent randomized study suggests that the best results with regards TTP are when the vaccine is given first and anti-androgen (AA) treatment added in after 6 months if the PSA is still climbing. The TTP difference in this arm was 26 months when compared to 16 months in the arm that got AA therapy first (Arlen et al., 2005).

In addition to the above there are DNA vaccines being developed, at least two using PSMA as the antigen. Early studies often used cell lysates which do not appear as effective as irradiated whole cells. Today the commonest cell-based vaccine is the DC technique, as used by Dendreon. However, it is a very labor and material expensive way of expanding and priming auto-logous APCs. The technique is excellent as a research tool but still requires an antigen for it to present. Trials have been conducted using peptides, proteins, mRNA, whole cells, lysates, and so on. There are over 300 DC trials in the literature which all use different details in the protocols. However, a number of generalizations can be made:

1. There are occasional spectacular clinical responses in virtually all tumor types. Unfortunately, these appear to be uncommon.

2. The most effective outcome would appear to be stable disease in young and generally fit patients.

3. Immunotherapy may be synergistic with other modalities of treatment.

(For further reviews see Grunebach et al., 2005; Nestle et al., 2005.)

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