Effect Of Immune Checkpoint Blockade Research Articles

Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18.

Recent clinical trials and animal models demonstrated that immune checkpoint blockade enhanced effector cell responses and tumor rejection; however, further development and improvement of cancer immunotherapy is necessary for more favorable objective responses. In this study, we examined the effect of IL18 on the antitumor effect of immune checkpoint inhibitors. We examined the effect of IL18 on the peritoneal dissemination of CT-26 cells or tail vein injection metastasis of B16/F10 cells using antiprogrammed death-1 ligand-1 (αPD-L1) and/or anti-CTL-associated antigen-4 (αCTLA-4) mAbs. Massive ascites developed after intraperitoneal inoculation of CT-26, resulting in animal death within 30 days. Treatment of mice with αPD-L1 and/or αCTLA-4 significantly prolonged their survival, and a combination of the antibodies and IL18 provided a much greater therapeutic benefit. The combination modality led to the accumulation of precursor of mature natural killer (pre-mNK) cells in the peritoneal cavity together with increased CD8(+) T and decreased CD4(+)CD25(+)Foxp3(+) T cells. Depletion of the pre-mNK cells abrogated the therapeutic effects and increased the number of CD4(+)CD25(+)Foxp3(+) T cells. The combination treatment also suppressed tail vein injection metastasis of B16/F10 cells. The results demonstrated that IL18 enhanced therapeutic effects of immune checkpoint blockade against peritoneal dissemination of carcinoma or tail vein injection metastasis of melanoma through accumulation of pre-mNK cells, memory-type CD8(+) T cells, and suppression of CD4(+)CD25(+)Foxp3(+) T cells. A combination of immune checkpoint inhibitors with IL18 may give a suggestion to the development of next-generation cancer immunotherapy. Clin Cancer Res; 22(12); 2969-80. ©2016 AACR.

Real-time monitoring of tumor progression and drug responses in a preclinical mouse model of prostate cancer.

Monitoring disease progression through imaging is playing an increasingly important role in the treatment of prostate cancer. Here, we report that primary mouse prostate cancer cell lines stably expressing luciferase and tumor biomarkers can be monitored through bioluminescence imaging along with assays of serum biomarkers and immune function. Tumorigenesis in immunocompetent C57BL/6 mice can be monitored in by collecting samples from the dorsal flank, dorsolateral prostate, and tail vein to obtain real-time subcutaneous, orthotopic, and metastasis indicators, respectively. We used this technique to confirm the therapeutic effect of immune checkpoint blockade. Our findings suggest the presented indicators are ideally suited for real-time tracking of drug responses, tumor progression and immune function.

Abstract B014: BGB324, a selective small molecule inhibitor of the receptor tyrosine kinase AXL, enhances immune checkpoint inhibitor efficacy

Abstract Signaling via the AXL receptor tyrosine kinase is a key suppressor of anti-tumor innate immune response. AXL is expressed on several cells associated with the suppressive tumor immune microenvironment including natural killer cells, dendritic cells and tumor-associated macrophages. AXL is also an important regulator of tumor plasticity related to epithelial-to-mesenchymal transition (EMT) that contributes to anti-tumor immune evasion. Hence AXL signaling contributes uniquely to tumor intrinsic and microenvironmental immune suppression in tumors. We therefore evaluated whether blocking AXL signaling with BGB324, a selective clinical-stage small molecule Axl kinase inhibitor, enhances the effect of immune checkpoint blockade in syngeneic cancer mouse models that display limited immunogenicity. We measured the effect of BGB324 in combination with anti-CTLA-4 and anti-PD-1 in the mammary adenocarcinoma 4T1/Balb/C syngeneic mouse model. BGB324 (50 mg/kg bid) significantly enhanced responsiveness to anti-CTLA-4/anti-PD-1 treatment (10 mg/kg of each, 4 doses) in Balb/C mice bearing 4T1 tumors. The combination of BGB324 + anti-CTLA-4/anti-PD-1 resulted in complete tumor clearance in 46.1 % of mice versus complete tumor clearance in 11.7 % of the mice treated with anti-CTLA-4/anti-PD-1 (p = 0.0087). BGB324 + anti-CTLA-4/anti-PD-1 treated tumors displayed enhanced CD8+ T cell tumor infiltration. Combination of BGB324 with immune checkpoint inhibitors is being evaluated in additional models, and detailed interrogation of AXL-dependent immune effector cell activity in tumors is in progress. In conclusion, AXL inhibition represents a unique opportunity to target anti-tumor immune suppressive mechanisms and supports clinical translation of BGB324 in combination with cancer immunotherapy in human cancer. Citation Format: Gro Gausdal, Kjersti Davidsen, Katarzyna Wnuk-Lipinska, Kathleen Wiertel, Monica Hellesøy, Magnus Blø, Lavina Ahmed, Linn Hodneland, Sergej Kiprijanov, Rolf A Brekken, James B Lorens. BGB324, a selective small molecule inhibitor of the receptor tyrosine kinase AXL, enhances immune checkpoint inhibitor efficacy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B014.

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The dramatic and long durable anti-tumor effect of immune checkpoint blockade, such as anti-CTLA-4 Ab, anti-PD-1 Ab, and anti-PD-L1 Ab was surprised the world. In addition, CAR-T cell therapy that target the CD19 indicates a very high response rate to the CD19-positive hematologic malignancies. Now, no one doubts the presence of immunity against cancer.Further, accordingly, tumor-specific neoantigen are attention now, the clinical trials of individualized peptide vaccination that target patient individual neoantigens has begun in the Western. On the other hand, the peptide vaccine therapy that target common self-antigen is not yet been approved in Japan, the development is struggling.In this paper, I overview the cancer immunotherapy and neoantigen and introduce some development of cancer immunotherapy in Japan.

Abstract PR05: Combination therapy with anti-CTLA4 and anti-PD1 leads to distinct immunologic changes in-vivo

Abstract Therapies targeting T cell immune checkpoints such as CTLA4 and PD1/PDL1 axis have shown considerable promise in the therapy of human cancer. Combination therapy with dual immune checkpoint blockade (ICB) was recently shown to be highly active in melanoma. While signaling via both PD1 and CTLA4 is known to converge downstream and dampen T cell function, data comparing in vivo effects of blockade of these immune checkpoints either alone or in combination in vivo in humans are limited. Here we have analyzed paired pre/post therapy samples from patients treated either anti-CTLA4 (n=5) or anti-PD1 (n=6) alone, or a combination of anti-CTLA4 and anti-PD1 (n=8), using several methodologies including multi-parameter flow cytometry, single-cell mass-cytometry (CyTOF), Luminex and analysis of transcriptome of purified immune cells with exon-level arrays. We show that blockade of CTLA4, PD1 or combination blockade leads to distinct immunologic, genomic and cytokine signatures in vivo. CTLA4 blockade leads to a prominent proliferation signature in vivo, manifest as an increase in Ki-67 expression in a subset of T cells with transitional memory phenotype. PD1 blockade does not induce this phenotype and instead leads to marked changes in T cells expressing NK and cytolysis associated genes, as exemplified by Granzyme+ T cells. Combination blockade leads to non-overlapping changes in gene expression including proliferation-associated and chemokine genes and leads to an increase in both Ki67+and Granzyme+ T cells. Overall, therapy-induced changes are more prominent in T cells than in monocytes include also involve non-overlapping changes in several alternatively-spliced transcripts, and non-coding RNAs. Each of the ICB therapies also leads to a distinct cytokine profile with differential effects on systemic levels of sIL2R and IL1a. Changes seen in the peripheral blood T cells can also be seen in the tumor infiltrating lymphocytes. Combination therapy leads to an increase in interferon-gamma; producing T cells in both circulation as well as tumor bed. PD1 expression is higher on tumor infiltrating T cells when compared to T cells in circulation. Importantly, PD1 receptor occupancy following anti-PD1 therapy may be incomplete in the tumor infiltrating T cells even in the setting of complete receptor occupancy in circulating T cells. These data demonstrate that blockade of PD1, CTLA4 alone or in combination have distinct immunologic effects in vivo and each strategy serves as a unique immune-therapeutic. Improved understanding of the in vivo effects of ICB is needed for rational development of future immune-based combinations against cancer. This abstract is also being presented as Poster B06. Citation Format: Rituparna Das, Rakesh Verma, Mario Sznol, Chadra Sekhar Boddupalli, Scott Gettinger, Harriet Kluger, Madhav Dhodapkar, Kavita Dhodapkar. Combination therapy with anti-CTLA4 and anti-PD1 leads to distinct immunologic changes in-vivo. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr PR05.

PD-1 blockade reverts motility arrest of transferred tumor-infiltrating CD8+ T cells in adoptive cell transfer immunotherapy (TUM7P.1014)

Abstract Adoptive cell transfer (ACT) immunotherapy can result in complete responses in the treatment of metastatic solid cancers, however the majority of patients eventually progress. Although many immune regulatory programs are context-dependent, the in vivo behavior of adoptively-transferred CD8+ T cells over time remains unknown. Using the Pmel-1 model, we performed intravital microscopy of subcutaneous tumors in mice to visualize the in vivo motility of transferred tumor-specific CD8+ T cells. This revealed that CD8+ T cell motility arrest increased over time after adoptive transfer. By ex vivo analyses, behavioral change coincided with a reduction in IFN-γ production and glucose uptake. As the transferred cells strongly expressed PD-1, we treated mice with both ACT and anti-PD-1 blocking antibody to determine the effect of immune checkpoint blockade on cellular motility. In mice treated with anti-PD-1 blocking antibody, transferred intratumoral CD8+ T cell motility arrest diminished, as compared with controls. This corresponded with an increase in CD8+ T cell glucose uptake. These data demonstrate that intratumoral CD8+ T cell behavior in ACT is dynamic and that greater motility is associated with increased functionality and bioenergetic demand. Furthermore, concurrent PD-1 blockade exerts a cell-intrinsic effect on transferred CD8+ T cells suggesting synergy between ACT and anti-PD-1 immunotherapy and the potential for their combinatorial use in the treatment of cancer

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<h3>Summary</h3> How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4⁺ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new <i>in vivo</i> model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy. <h3>Key Points</h3> TCR signal strength-dependent programming of CD4⁺ T cells revealed over time in vivo Inhibitory receptor expression is dynamic, TCR signal strength dependent, and rapidly re-calibrates T cell activation thresholds PD1 but not Lag3 blockade leads to a unique and increased TCR signal strength signature (coined TCR.strong) TCR.strong metric stratifies melanoma patient survival in response to Nivolumab (anti-PD1) therapy