Growth Of Established Subcutaneous Tumors Research Articles

Abstract 5089: Antitumor activities elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1

Abstract Interleukin (IL)-28A/IFN-λ2 and IL-29/IFN-λ1 have been demonstrated to elicit direct and indirect antitumor actions. In this study, we constructed an adenovirus vector expressing either IL-28A/IFN-λ2 (AdIL-28A) or IL-29/IFN-λ1 (AdIL-29) to evaluate the therapeutic properties of intratumoral injection of recombinant adenovirus to apply for the clinical implementation of cancer gene therapy. Despite the lack of antiproliferative effect on MCA205 and B16-F10 cells, a retarded growth of established subcutaneous tumors was observed following multiple injections of either AdIL-28A or AdIL-29 when compared with AdNull. In vivo cell depletion experiments displayed that both NK cells and CD8+ T cells play a major role in AdIL-28A-mediated tumor growth suppression. A significant increase in the number of infiltrating CD8+ T cells into the tumors treated with either AdIL-28A or AdIL-29 was observed. Moreover, specific antitumor cytotoxic T lymphocyte reactivity was detected in spleen cells from animals treated with either AdIL-28A or AdIL-29. In IFN-γ deficient mice, the antitumor activity of AdIL-28A was completely impaired, indicating that IFN-γ is critically involved in the tumor growth inhibition triggered by AdIL-28A. IL-12 provided an additive antitumor effect when combined with AdIL-28A. These results indicate that AdIL-28A and AdIL-29 could be successfully utilized as an alternative cancer gene therapy. Note: This abstract was not presented at the meeting. Citation Format: Muneo Numasaki, Hiroki Tsukamoto, Yoshihisa Tomioka. Antitumor activities elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5089. doi:10.1158/1538-7445.AM2017-5089

Anti-tumor immunity elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1.

Interleukin (IL)-28A/interferon (IFN)-λ2 and IL-29/IFN-λ1 have been demonstrated to elicit direct and indirect anti-tumor actions. In this study, we constructed an adenovirus vector expressing either IL-28A/IFN-λ2 (AdIL-28A) or IL-29/IFN-λ1 (AdIL-29) to evaluate the therapeutic properties of intratumoral injection of recombinant adenovirus to apply for the clinical implementation of cancer gene therapy. Despite the lack of an anti-proliferative effect on MCA205 and B16-F10 cells, a retarded growth of established subcutaneous tumors was observed following multiple injections of either AdIL-28A or AdIL-29 when compared with AdNull. In vivo cell depletion experiments displayed that both NK cells and CD8(+) T cells have a major role in AdIL-28A-mediated tumor growth suppression. A significant increase in the number of infiltrating CD8(+) T cells into the tumors treated with either AdIL-28A or AdIL-29 was observed. Moreover, specific anti-tumor cytotoxic T lymphocyte reactivity was detected in spleen cells from animals treated with either AdIL-28A or AdIL-29. In IFN-γ-deficient mice, anti-tumor activities of AdIL-28A were completely impaired, indicating that IFN-γ is critically involved in the tumor growth inhibition triggered by AdIL-28A. IL-12 provided a synergistic anti-tumor effect when combined with AdIL-28A. These results indicate that AdIL-28A and AdIL-29 could be successfully utilized as an alternative cancer immunogene therapy.

Abstract B198: Pharmacological profile of the PGE2 EP4 receptor antagonist E7046

Abstract E7046 is a potent and selective small molecule antagonist of the type 4 prostaglandin E2 (PGE2) receptor EP4. The discovery and evaluation of this novel EP4 antagonist for cancer treatment was recently presented at the AACR 2015 annual conference (abstract # 275). Here we show new evidence of E7046 in vivo activity against a series of syngeneic tumor models as well as its pharmacological effect on APCMin/+ mice, which possess a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene. We found that daily oral administration of E7046 was able to both slow down the growth of established subcutaneous tumors and significantly delay the recurrence of tumors after surgical resection. These activities of E7046 correlated with differences in the immune cell composition of the microenvironments of each type of tumor. In this context, cyclooxygenase 2 - positive (COX-2+) tumors that were rich in myeloid cells showed an enhanced response to E7046 regardless of their T lymphocyte infiltration status. In addition, E7046 was superior to the COX-2 inhibitor celecoxib against mutant APC-driven neoplastic polyp formation in the intestines of APCMin/+ mice exposed to dextran sodium sulfate. Using the APCMin/+ mouse model, we found that E7046 significantly reduced the combined colon polyp area and the size of individual polyps without influencing the total polyp number. For each of these parameters, E7046 activity against colon and small intestine tumors was greater than that of a comparable dose of celecoxib. Quantification of cyclin D1 staining in colon and small intestine polyps further indicated that both compounds led to a significant reduction in the proliferation of tumor cells, with a greater effect for E7046 compared to celecoxib. Overall, these preclinical results suggest that this agent should be further investigated in patients with COX-2+ tumors infiltrated with myeloid cells, including patients with APC-mutated colon cancer. First-In-Human study of E7046 is currently enrolling patients (IND 125272). Citation Format: Diana I. Albu, Jiayi Wu, Kuan-chung Huang, Renee Wright-Michaud, Shanqin Xu, Galina Kuznetsov, Xingfeng Bao, Mary Woodall-Jappe. Pharmacological profile of the PGE2 EP4 receptor antagonist E7046. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B198.

Induction of anti-tumor immunity by vaccination with dendritic cells pulsed with anti-CD44 IgG opsonized tumor cells.

Due to the pivotal role that dendritic cells (DC) play in eliciting and maintaining functional anti-tumor T cell responses, these APC have been exploited against tumors. DC express several receptors for the Fc portion of IgG (Fcgamma receptors) that mediate the internalization of antigen-IgG complexes and promote efficient MHC class I and II restricted antigen presentation. In this study, the efficacy of vaccination with DC pulsed with apoptotic B16 melanoma cells opsonized with an anti-CD44 IgG (B16-CD44) was explored. Immature bone marrow derived DC grown in vitro with IL-4 and GM-CSF were pulsed with B16-CD44. After 48 h of pulsing, maturation of DC was demonstrated by production of IL-12 and upregulation of CD80 and CD40 expression. To test the efficacy of vaccination with DC+B16-CD44, mice were vaccinated subcutaneously Lymphocytes from mice vaccinated with DC+B16-CD44 produced IFN-gamma in response to B16 melanoma lysates as well as an MHC class I restricted B16 melanoma-associated peptide, indicating B16 specific CD8 T cell activation. Upon challenge with viable B16 cells, all mice vaccinated with DC alone developed tumor compared to 40% of mice vaccinated with DC+B16-CD44; 60% of the latter mice remained tumor free for at least 8 months. In addition, established lung tumors and distant metastases were significantly reduced in mice treated with DC+B16-CD44. Lastly, delayed growth of established subcutaneous tumors was induced by combination therapy with anti-CD44 antibodies followed by DC injection. This study demonstrates the efficacy of targeting tumor antigens to DC via Fcgamma receptors.

Tumor suppression and therapy sensitization of localized and metastatic breast cancer by adenovirus p53.

We have examined the effects of a replication-defective adenovirus encoding p53 (RPR/INGN 201 [Ad5CMV-p53]; Adp53), alone or in combination with the breast cancer therapeutic doxorubicin (Adriamycin), to suppress growth and induce apoptosis in breast cancer cells in vitro. We have also examined the in vivo effect of intratumoral administration of Adp53, alone or in combination with doxorubicin, to suppress the growth of established subcutaneous MDA-MB-435 breast cancer tumors. Finally, using the MDA-MB-435 orthotopic model of metastatic breast cancer, we have examined the effect of systemic administration of Adp53, alone or in combination with doxorubicin, to reduce the incidence of metastases. We find that whereas in vitro treatment of cells with Adp53 reduces [(3)H]thymidine incorporation by about 90% at 48 hr, cell viability at 6 days is reduced by only some 50% relative to controls. Although apoptosis is detectable in Adp53-treated cultures, these results suggest that a large fraction of Adp53-treated cells merely undergo reversible cell cycle arrest. Combined treatment with Adp53 and doxorubicin results in a greater than additive loss of viability in vitro and increased apoptosis. In vivo, locally administered Adp53 suppresses growth of established subcutaneous tumors in nude mice and suppression is enhanced by doxorubicin. In the metastatic breast cancer model, systemic administration of Adp53 plus doxorubicin leads to a significant reduction in the incidence of metastases relative to Adp53 or doxorubicin alone. Taken together, these data indicate an additive to synergistic effect of Adp53 and doxorubicin for the treatment of primary and metastatic breast cancer.

Spleen‐derived dendritic cells engineered to enhance interleukin‐12 production elicit therapeutic antitumor immune responses

The major goal in cancer immunotherapy is the induction of tumor-specific T lymphocytes capable of killing tumor cells. As both dendritic cells (DCs) and interleukin-12 (IL-12) can play immunostimulatory roles in vivo, the use of a combination of these has become a promising approach. In the present study, we used a murine tumor model to examine whether spleen-derived DCs transduced with the IL-12 gene could elicit tumor-specific immune responses. BALB/c mice injected peritumorally with adenovirus-mediated IL-12 gene-transduced antigen-unpulsed DCs inhibited the growth of day 5-established subcutaneous CT26 tumors. Splenocytes from treated mice responded specifically to parental tumor cells and showed increased production of interferon gamma (IFN-γ) and antitumor cytotoxic T-lymphocyte (CTL) activity. Increased numbers of both CD4+ and CD8+ T cells were detected in the treated tumors. The inhibition of tumor growth was significantly greater in mice injected with IL-12 gene-transduced DCs than in those injected with IL-12 gene-transduced fibroblasts or the IL-12 gene-encoding adenovirus itself. Taken together, these results indicate that DCs transduced with the IL-12 gene by a recombinant adenovirus are effective in inducing tumor-specific Th1 and CTL responses that inhibit the growth of established subcutaneous tumors. Int. J. Cancer 87:665–672, 2000. © 2000 Wiley-Liss, Inc.

Spleen-derived dendritic cells engineered to enhance interleukin-12 production elicit therapeutic antitumor immune responses

The major goal in cancer immunotherapy is the induction of tumor-specific T lymphocytes capable of killing tumor cells. As both dendritic cells (DCs) and interleukin-12 (IL-12) can play immunostimulatory roles in vivo, the use of a combination of these has become a promising approach. In the present study, we used a murine tumor model to examine whether spleen-derived DCs transduced with the IL-12 gene could elicit tumor-specific immune responses. BALB/c mice injected peritumorally with adenovirus-mediated IL-12 gene-transduced antigen-unpulsed DCs inhibited the growth of day 5-established subcutaneous CT26 tumors. Splenocytes from treated mice responded specifically to parental tumor cells and showed increased production of interferon gamma (IFN-gamma) and antitumor cytotoxic T-lymphocyte (CTL) activity. Increased numbers of both CD4(+) and CD8(+) T cells were detected in the treated tumors. The inhibition of tumor growth was significantly greater in mice injected with IL-12 gene-transduced DCs than in those injected with IL-12 gene-transduced fibroblasts or the IL-12 gene-encoding adenovirus itself. Taken together, these results indicate that DCs transduced with the IL-12 gene by a recombinant adenovirus are effective in inducing tumor-specific Th1 and CTL responses that inhibit the growth of established subcutaneous tumors.

Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. III. Inhibition of growth and necrosis of tumors implanted subcutaneously.

Administration of highly purified interferon to DBA/2 mice inhibited the growth of interferon-sensitive or interferon-resistant Friend erythroleukemia cells implanted subcutaneously. Injection of interferon at the site of tumor inoculation was more effective than injection of interferon intraperitoneally. Histologic examination of tumors in interferon-treated mice showed extensive areas of tumor-cell necrosis in the absence of an obvious host-cell infiltrate. Interferon inhibited the growth of established subcutaneous tumors and induced complete tumor regression in some mice. Interferon treatment also resulted in an inhibition of tumor metastases in the liver and spleen.