AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression.

AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models. Tumor control and survival benefit were associated with enhanced antitumor immunity. VIC-008 augmented mesothelin-specific CD8+ T-cell responses in the spleen and lymph nodes and facilitated intratumoral lymphocytic infiltration. However, VIC-008 treatment was associated with increased programmed cell death protein-1 (PD-1) expression on intratumoral CD8+ T cells, likely due to high CXCL12 in the tumor microenvironment. AMD3100 alone and in combination with VIC-008 modulated immunosuppression in tumors and the immune system through suppression of PD-1 expression on CD8+ T cells and conversion of regulatory T cells (Tregs) into CD4+CD25-Foxp3+IL2+CD40L+ helper-like cells. In mechanistic studies, we demonstrated that AMD3100-driven Treg reprogramming required T cell receptor (TCR) activation and was associated with loss of PTEN due to oxidative inactivation. The combination of VIC-008 augmentation of tumor-specific CD8+ T-cell responses with AMD3100 abrogation of immunosuppression conferred significant benefits for tumor control and animal survival. These data provide new mechanistic insight into AMD3100-mediated immunomodulation and highlight the enhanced antitumor effect of AMD3100 in combination with a tumor antigen-targeted therapy in mouse malignant mesothelioma, which could be clinically relevant to patients with this difficult-to-treat disease. Cancer Immunol Res; 6(5); 539-51. ©2018 AACR.

Li B ，Zeng Y ，Reeves PM ，Ran C ，Liu Q ，Qu X ，Liang Y ，Liu Z ，Yuan J ，Leblanc PR ，Ye Z ，Sluder AE ，Gelfand JA ，Brauns TA ，Chen H ，Poznansky MC ... -  《-》

Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.

Zeng Y ，Li B ，Liang Y ，Reeves PM ，Qu X ，Ran C ，Liu Q ，Callahan MV ，Sluder AE ，Gelfand JA ，Chen H ，Poznansky MC ... -  《-》

A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma.

Yuan J ，Kashiwagi S ，Reeves P ，Nezivar J ，Yang Y ，Arrifin NH ，Nguyen M ，Jean-Mary G ，Tong X ，Uppal P ，Korochkina S ，Forbes B ，Chen T ，Righi E ，Bronson R ，Chen H ，Orsulic S ，Brauns T ，Leblanc P ，Scholler N ，Dranoff G ，Gelfand J ，Poznansky MC ... -  《Journal of Hematology & Oncology》

Surgical cytoreduction restores the antitumor efficacy of a Listeria monocytogenes vaccine in malignant pleural mesothelioma.

Recent studies suggest that immunotherapy may offer a promising treatment strategy for early-stage malignant pleural mesothelioma (MPM), but advanced tumor burden may limit the efficacy of immunotherapy. Therefore, we hypothesized that surgical cytoreduction could restore the efficacy of vaccine-based immunotherapy for MPM. We developed a murine model of MPM through transduction of a mesothelioma cell line with mesothelin. We used this model to evaluate the efficacy of a Listeria monocytogenes vaccine expressing mesothelin. Tumor growth was significantly inhibited at four weeks in animals vaccinated two weeks prior to tumor cell inoculation as compared to those given an empty vector control (1371 ± 420 mm(3) versus 405 ± 139 mm(3); p < 0.01). Mice vaccinated one week prior to tumor challenge also displayed significant reduction in tumor volume (1227 ± 406 mm(3) versus 309 ± 173 mm(3); p < 0.01). The vaccine had no effect when administered concurrently with tumor challenge, or after tumors were established. Flow cytometry showed reduced mesothelin expression in large tumors, as well as tumor-associated immunosuppression due to increased myeloid derived suppressor cells (MDSCs). These factors may have limited vaccine efficacy for advanced disease. Surgical cytoreduction of established tumors restored the antitumor potency of the therapeutic vaccine, with significantly reduced tumor burden at post-operative day 18 (397 ± 103 mm(3) versus 1047 ± 258 mm(3); p < 0.01). We found that surgery reduced MDSCs to levels comparable to those in tumor-naïve mice. This study demonstrates that cytoreduction surgery restores the efficacy of cancer vaccines for MPM by reducing tumor-related immunosuppression that impairs immunotherapy.

Kennedy GT ，Judy BF ，Bhojnagarwala P ，Moon EK ，Fridlender ZG ，Albelda SM ，Singhal S ... -  《-》

Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy.

Kim S ，Buchlis G ，Fridlender ZG ，Sun J ，Kapoor V ，Cheng G ，Haas A ，Cheung HK ，Zhang X ，Corbley M ，Kaiser LR ，Ling L ，Albelda SM ... -  《-》