by ecancer reporter Clare Sansom

Recent clinical trials have shown that therapeutic cancer vaccines, which stimulate patients’ own immune responses against their tumours, can be effective in prolonging survival with few side effects.

There are, however, still many challenges involved in their development. It is difficult to predict which tumour antigens will be most effectively targeted by vaccines and to predict an individual patient’s response, and the regulatory environment can still be hostile to immunotherapies.

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and it has a poor prognosis unless detected early: only about 10% of those diagnosed with Stage IV disease survive for five years.

Clinical trials have suggested, however, that it can respond well to immunotherapy. Harpreet Singh-Jasuja from Immatics Biotechnologies GmbH, Tübingen, Germany has now led a large, international team of researchers in designing, developing and testing a therapeutic cancer vaccine that uses peptide antigens expressed on the surface of RCC cells.

This vaccine, named IMA901, has been proved effective in maintaining disease control and prolonging survival in Phase I and Phase II clinical trials.

Singh-Jasuja and his colleagues used the antigen discovery platform XPRESIDENT to select multiple peptides from antigens expressed on the surface of RCC cells by comparing the mRNA profiles of renal cell tumours to those of healthy tissues.

Nine HLA-A*02–restricted tumour-associated peptides and one HLA-DR restricted peptide were selected to be incorporated in the test vaccine IMA901 based on T-cell responses in healthy donors. One marker peptide from the hepatitis B virus was added to the vaccine for the Phase I study only.

In that Phase I study, 28 patients with advanced RCC who carried the HLA-A*02 allele received up to eight doses of IMA901, each preceded by an immunomodulator, GM-CSF. Eleven patients had stable disease during the three-month study period; there was one partial response and no serious treatment-related adverse events or deaths.

A vaccine-induced T-cell response to at least one peptide was observed in twenty patients, with eight responding to multiple peptides and 14 to the marker peptide.

Tumour progression was significantly less likely in those patients who responded to multiple tumour-associated peptides. There was also a negative correlation between numbers of regulatory T cells (T_reg cells) measured before therapy and response to the vaccine.

Sixty-eight patients with metastatic RCC, again all carrying the HLA-A*02 allele, were recruited into the Phase II study. All these patients received the IMA901 vaccine; they were randomised 1:1 to receive either pre-treatment with cyclophosphamide, which can inhibit T_reg cells, or no such pre-treatment. Serious adverse effects were extremely rare throughout the trial.

Only one complete and two partial responses were recorded, but stable disease was more common, particularly in the cyclophosphamide arm: 31% (95% confidence interval 17-48%) of patients who received cyclophosphamide and 14% (95% confidence interval 3-35%) of those who did not had stable disease or better six months after starting treatment.

The median overall survival of patients receiving cyclophosphamide was 23.5 months compared with 14.8 months for those who did not.

The immune responses of 61 of the patients were monitored throughout the study; a total of 64% of these patients in both arms showed an immune response to one or more of the peptides. Cyclophosphamide treatment was correlated with longer overall survival only in those patients with immune responses, suggesting that this drug acts as an immuno-modulator to potentiate the vaccine rather than having an independent anti-tumour effect.

Survival was longest in those patients who responded to more than one peptide, and a reduction in T_reg cell numbers was observed in the patients who received cyclophosphamide. Finally, the researchers analysed cell and serum biomarkers in all patients. High concentrations of two serum biomarkers, apolipoprotein A-I and chemokine (C-C motif) ligand 17, were found to correlate with both immune response and longer survival in the cyclophosphamide arm only.

Taken together, these results suggest that IMA901 is likely to be effective in advanced renal cell carcinoma in patients bearing appropriate HLA alleles; this is the first vaccine composed of HLA-restricted peptides to show such an effect in this tumour.

A Phase III trial[1] of IMA901 and cyclophosphamide in metastatic RCC is under way.

Source: Walter, S., Weinschenk, T., Stenzl, A. and 36 others (2012). Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nature Medicine, published online ahead of print 29 July 2012. doi:10.1038/nm.2883