James Allison of the University of Texas MD Anderson Cancer Center and Robert Schreiber of the Washington University School of Medicine were cited for their work on antibody treatments that has increased the survival of patients with metastatic melanoma.
Other winners included Indian economist Bina Agarwal, a professor at the University of Manchester, recognised in the gender studies category for her "heroic" work studying women's contributions to agriculture in India.
Germans Aleida and Jan Assmann, a married couple was recognised for their work presenting collective memory "as a requirement for the formation of the identity of religious and political communities."
The Balzan Foundation awards two prizes in the sciences and two in the humanities each year, rotating specialties to highlight new or emerging areas of research and sustain fields that might be overlooked elsewhere.
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Recipients receive 750,000 Swiss francs (USD 790,000), half of which must be used for research, preferably by young scholars or scientists.
This year, the Balzan Foundation also awarded a fifth prize, in international relations, which was deferred from last year after the committee failed to reach agreement on a winner.
It went to Robert O Keohane of the Woodrow Wilson School at Princeton University, best known for his influential 1984 book "After Hegemony: Cooperation and Discord in the World Political Economy."