Background: Cancers deficient in DNA mismatch repair (dMMR) are highly immunogenic tumors exhibiting high rates of response to immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) interaction. These tumors are characterized by high levels of microsatellite instability (MSI-H) and an exceptionally high tumor mutation burden, thought to underlie responsiveness to immunotherapy, with higher predicted immunogenicity of mutation-associated neoantigens. However, primary and acquired resistance are observed and diversity in responses is not fully explained by variations in mutation burden. Other immune checkpoints may be acting in parallel with PD-1/PD-L1. In particular, lymphocyte activation gene 3 (LAG3) mediates exhaustion of activated T cells and may have a role in resistance to PD-(L)1 inhibitors (PD-(L)1i); therefore, we hypothesized that the addition of LAG3 inhibitor (relatlimab) to the PD-1i nivolumab may overcome resistance in these tumors. Methods: Patients with advanced dMMR/MSI-H cancer who have progressive disease (by RECIST 1.1) during or within 6 months of PD-(L)1i containing therapy, and after at least 12 weeks of therapy, and meet other eligibility will be enrolled. All patients will receive nivolumab 480mg + relatlimab 160mg every 4 weeks until intolerance or progression, or up to a maximum of 2 years. The primary endpoint is objective response rate. Key secondary endpoints include safety, progression free and overall survival, and other response endpoints as measured by RECIST 1.1 and iRECIST criteria. Exploratory objectives will include analysis of the tumor microenvironment on biopsies obtained at baseline and on-treatment, analysis of T cell populations in the tumor and in the periphery and functional characterization of mutation-associated neoantigen-specific T cells. Studies of the microbiome will be conducted on stool and oral wash samples. Enrollment of 21 patients is planned. Clinical trial information: NCT03607890