Tumor-Associated Antigen Expressing Listeria monocytogenes Induces Effective Primary and Memory T-Cell Responses Against Hepatic Colorectal Cancer Metastases

Abstract

PurposeDespite advances in therapy for the treatment of metastatic colorectal cancer, many patients die of hepatic disease. Current immunotherapeutic strategies are likely limited by inhibitory signals from the tumor. To successfully eliminate tumor deposits within an organ, an appropriate immunologic milieu to amplify antitumor responses must be developed.MethodsWe used a murine model utilizing the CT26 colon cancer cell line to analyze primary and memory tumor-specific T-cell responses induced by an attenuated actin A and internalin B deleted immunodominant tumor-associated antigen expressing strain of Listeria monocytogenes for the treatment of metastatic colorectal cancer.ResultsTreatment of mice bearing established hepatic metastases with this L. monocytogenes strain led to the generation of a strong initial tumor-specific cytotoxic CD8+ T-cell response that successfully treated 90% of animals. Tumor antigen-specific central and effector memory T cells were also generated and protected against tumor rechallenge. These cell populations, when measured before and after tumor rechallenge, showed a marked expansion of antigen-specific effector CD8+ effector memory T cells. This strain of L. monocytogenes was able to down-modulate the expression of the immune checkpoint molecule, PD-1, within the tumor microenvironment but had variable effects on CTLA-4 expression.ConclusionsThis L. monocytogenes strain generated a highly effective antitumor T-cell response, providing a basis for the development of this vaccine platform in patients with liver metastases.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-011-2037-0) contains supplementary material, which is available to authorized users.

Immunotherapy for Brain Cancer: Recent Progress and Future Promise

“…GVAX has been safely administered in combination with CTLA-4 blockade (80), a combination that has demonstrated efficacy in preclinical models (65, 81) and combining GVAX with PD-1 blockade has been similarly promising (82). Although listeria vaccines are only beginning to be applied to GBM, this vaccine platform may prove particularly advantageous for combinatorial therapy as listeria vaccines can drive T-cell proliferation without PD-1 upregulation (83) and increase T effector to Treg ratios in the brain tumor microenvironment (Jackson, Lim, and Drake; unpublished data). In the process of translating these findings to a combinatorial clinical regimen, it should be noted that intracranial tumors might respond differently to listeria vaccination than peripheral tumors (84).…”

Augmented Macrophage Differentiation and Polarization of Tumor-associated Macrophages Towards M1 Subtype in Listeria-administered Tumor-bearing Host

“…[1][2][3][4] Thus, it is desirable to study host-pathogen relationship for therapeutic utilization of the benefits accruing from various components of immune system. Evidences suggest that Listeria infection, although is associated with remarkable modulatory effect on components of immune system, 2,4-6 much still remains to be understood with respect to its effect on suppressed myelopoiesis and functional status of tumorassociated macrophages (TAM) in a tumor-bearing host.…”

Listeria monocytogenes

“…19 In a metastatic model of hepatic colorectal cancer, an AH1 peptide-expressing Lm strain elicited potent cytotoxic tumorspecific CD8 + T cell responses that could cure mice of hepatic metastasis and subsequently protect from tumor re-challenge. 20 Recently, an Lm strain expressing and secreting a fusion of multiple peptides of the hepatocellular carcinoma (HCC)-related tumor-associated antigen was shown to slow the development of HCC in both prophylactic and therapeutic settings, demonstrating also the induction of strong cytotoxic T cell immunity against each epitope in the fusion peptide; this supports what we know regarding Lm's ability to overcome self-tolerance to an endogenous antigen. 21 While Lm is indeed capable of delivering a wide selection of proteins into the cells it infects, the versatility of Lm as a bacterial carrier system is further seen in its ability to also transport DNA into mammalian target cells, with the successful delivery of pro-drug converting enzymes by Lm into tumor cells having been reported.…”