The tumor environment contains all the ingredients needed to mount an anticancer immune response—tumor antigens, antigen presenting cells (APCs, including tumor-associated macrophages [TAMs] and dendritic cells), and T cells—but activation of the immune system to generate that antitumor response is complex and multifaceted.
By “taking the brakes off” the immune response, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many solid tumors. However, many patients never respond to these agents, and responders often develop resistance.
Potential reasons include a lack of preexisting anticancer T cells at the time of ICI administration or the inability of anticancer T cells to overcome the immunosuppressive tumor microenvironment (TME).
Lerapolturev is an investigational immunotherapy based on the live attenuated Sabin type 1 oral polio vaccine, genetically modified for safety. Lerapolturev targets cells using the poliovirus receptor, CD155, which is widely expressed on both the malignant cells of most solid tumors and APCs in the TME.
Activation of the MDA5 pathway by lerapolturev results in a sustained, robust release of type I and type III interferons—the precise profile known to be required to generate an anticancer immune response.4,5 It also results in minimal release of unwanted cytokines associated with severe cytokine release syndrome.6
Because of lerapolturev’s genetic modifications, lerapolturev infection of APCs is nonlethal and results in enhanced interaction with and activation of APCs rather than death. Infection of APCs by lerapolturev stimulates a specific pathway in the innate immune system known as MDA5 that responds specifically to double-stranded RNAs, which are produced during replication of RNA viruses, including lerapolturev.1-3
In vitro data demonstrate that lerapolturev induces robust activation of dendritic cells7 and monocyte-derived macrophages.3 Lerapolturev treatment in tumor slice models leads to activation of CD4 and CD8 T cells with a distinct, polyfunctional phenotype.3 Tumor-infiltrating CD4 T cells induced by lerapolturev express high levels of the cytolytic effector granzyme B (GzmB) and T-bet, a Th1-promoting transcription factor that also supports T cell function; CD8 T cells induced by lerapolturev expressed higher levels of GzmB and interferon gamma (IFN-γ).3Infiltration of the tumor with activated, polyfunctional T cells plays a crucial role in the anticancer immune response.
Infant vaccination against poliovirus is nearly universal. Additionally, patients are boosted with an inactivated polio vaccine prior to treatment with lerapolturev. The resulting strong, preexisting immunity against poliovirus, and therefore lerapolturev, is potentially synergistic with the sustained type-I/III IFN response induced by lerapolturev infection of APCs. Preclinical studies identify a robust influx of tumor-associated CD4 and CD45 T cells and increased markers of T cell function following poliovirus immunization and intratumoral lerapolturev treatment.
In preclinical studies, lerapolturev generated robust antitumor T cell memory as demonstrated by adoptive transfer studies.3
Addition of lerapolturev to anti–PD-1 leads to an improved immune response in a mouse B16 melanoma model in which a CD155 transgene allows for lerapolturev to infect murine cells.3,6 These data point to the potential for lerapolturev to induce an improved anticancer response when combined with an anti–PD-1 ICI.
Clinical responses were observed in both injected and noninjected lesions during the phase 1 trial in advanced melanoma, suggesting a systemic antitumor immune response.8 This is being further evaluated in the ongoing LUMINOS-102 phase 2 trial.
Lerapolturev has been administered to more than 200 patients and is the subject of multiple ongoing phase 2 clinical trials across 6 potential solid tumor indications.