scholarly journals Interleukin 1-induced, T cell-mediated regression of immunogenic murine tumors. Requirement for an adequate level of already acquired host concomitant immunity.

1988 ◽  
Vol 168 (6) ◽  
pp. 2031-2043 ◽  
Author(s):  
R J North ◽  
R H Neubauer ◽  
J J Huang ◽  
R C Newton ◽  
S E Loveless
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Regression ◽  
Interleukin 1 ◽  
Host Immunity ◽  
Antitumor Action ◽  
Complete Regression ◽  
Subtherapeutic Level

Intraperitoneal injection of human rIL-1 in a dose of 0.5 microgram daily for 5 d, or 1 microgram daily for 3 d, was capable of causing complete regression of immunogenic SA1 sarcoma growing subcutaneously in syngeneic or semisyngeneic mice. Higher doses of IL-1 were not more therapeutic against the SA1 sarcoma, but needed to be given to cause complete regression of the immunogenic L5178Y lymphoma. On the other hand, the P815 mastocytoma was much less responsive to IL-1 therapy, in that it failed to undergo complete regression in response to doses of IL-1 capable of causing regression of the L5178Y lymphoma. IL-1 caused regression of the SA1 sarcoma when given on days 6-8 of tumor growth, but not when given on days 1-3. This refractoriness of a small tumor to IL-1 therapy suggests that the antitumor action of IL-1 is based on an underlying host-immune response that is not generated until after day 3 of tumor growth. Direct evidence for the participation of host immunity in IL-1-induced tumor regression was supplied by results showing that IL-1 was not therapeutic against the SA1 sarcoma growing in T cell-deficient (TXB) mice, unless these mice were first infused with Ly-2+ and L3T4+ T cells from donor mice bearing an established SA1 sarcoma. In contrast, normal T cells, or T cells from donor mice bearing a YAC-1 lymphoma, failed to provide TXB recipients with the ability to cause regression of their SA-1 sarcoma in response to IL-1 treatment. The results are in keeping with the interpretation that exogenous IL-1, by augmenting the production of tumor-sensitized T cells, converts a subtherapeutic level of host immunity to a therapeutic level. The results suggest, in addition, that IL-1 only stimulates the replication of T cells that are already engaged in the antitumor immune response.

Dipeptidyl Peptidase Inhibition Accelerates Dendritic Cell Cross Priming of Tumor-Reactive T Cells Resulting in Regression of Established Tumors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2579-2579
Author(s):  
Meghaan Walsh ◽  
Aviva C Krauss ◽  
Jessica PE Davis ◽  
Su Young Kim ◽  
Martin Guimond ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Regression ◽  
High Dose ◽  
Complete Regression ◽  
Tumor Bearing ◽  
Dc Vaccine ◽  
Dipeptidyl Peptidases

Abstract BACKGROUND: PT-100 is an aminoboronic dipeptide that competitively inhibits dipeptidyl peptidases. While PT-100 has no direct effect on tumor cells in vitro, it exhibits potent antitumor effects in vivo. We have shown that female C57BL/6 (B6) mice with MB49 tumors, which naturally express the male minor histocompatibility antigen complex (HY), are primed to HY, but the immune response is insufficient to control tumor growth. In this study, we used the well-characterized HY antigen system to examine the immunomodulatory effects of PT-100 during treatment-induced tumor regression. METHODS: B6 female mice were inoculated subcutaneously with MB49 (106 cells) on day 0 and treated daily with PT-100 by gavage. For re-challenge experiments mice received high dose MB49 (3×106 cells) three weeks after complete regression of primary tumors. IFN-g ELISPOT was used to measure HY antigen specific T cell responses in the spleen and lymph nodes (LNs) during tumor growth. For adoptive transfer experiments, T cells were magnetic-bead purified from LNs and spleens of tumor-bearing PT-100 treated, tumor-bearing sham treated, or naïve mice and injected intravenously into Rag1−/− recipients (1.2×106 cells) which were then inoculated with high dose MB49. T cells were depleted with monoclonal antibodies to CD4 and CD8. Dendritic cells (DCs) were depleted with diphtheria toxin (DT) in bone marrow chimeras expressing the DT receptor under the CD11c promoter. DC activation examined by flow cytometry. For vaccine experiments, HY-expressing DCs were cultured from male B6 bone marrow and injected intraperitoneally (1×105 cells). RESULTS: PT-100 treatment resulted in complete regression of MB49, even when limited to the first week (days 3–7) during tumor progression. Treatment started later than week 1 was insufficient to establish consistent, complete tumor regression. High-dose re-challenge of PT-100 treated mice resulted in initial growth followed by regression without additional PT-100. IFN-gELISPOT revealed a robust response against HY in spleens of controls on day 17. Interestingly, PT-100 treated mice had quantitatively similar priming, but the response peaked earlier (day 10), just prior to tumor regression. Purified T cells from PT-100 treated donors collected on day 17 mediated markedly enhanced tumor protection compared to recipients of T cells from sham treated tumor-bearing mice despite significantly more HY-reactive cells in the spleen and LNs of sham treated-tumor bearing mice by that time. T cell or DC depletion independently abrogated the anti-tumor effect of PT-100 and treatment with PT-100 increased CD80 and CD86 expression on LN DC populations in vivo. Although HY DC vaccination does not affect tumor growth, supplementation of the DC vaccine with PT-100 mediated a therapeutic effect resulting in regression of well-established tumors. CONCLUSIONS: PT-100 establishes a consistent and potent antitumor effect against MB49 dependent on T cells and DCs. Treatment results in a memory response that is protective against high dose MB49 re-challenge. PT-100-induced tumor regression is associated with enhanced early tumor priming, associated with increases in activated DCs. T cells from PT-100 treated mice elicit superior protection upon adoptive transfer compared to shams, despite quantitatively less tumor-primed T cells, suggesting the PT-100 antitumor effect may involve a qualitative difference in T cell function. PT-100 given as an adjuvant to a DC vaccine results in increased potency and regression of established tumors. Inhibition of dipeptidyl peptidases modulate naturally occurring anti-tumor immune responses and contribute to the generation of a therapeutic anti-cancer vaccine.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity.

1988 ◽  
Vol 168 (6) ◽  
pp. 2193-2206 ◽  
Author(s):  
M Awwad ◽  
R J North
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Regression ◽  
Cell Mediated Immunity ◽  
Complete Regression ◽  
Suppressor T Cells ◽  
Antibody Treatment ◽  
P815 Mastocytoma ◽  
Thymectomized Mice

This study shows that intravenous injection of 1 mg of anti-L3T4 mAb (GK1.5) into thymectomized mice bearing the syngeneic L5178Y lymphoma results, after a delay of 2-3 d, in complete regression of this tumor and in long-term host survival. A flow cytofluorometric examination of the spleen cells of mAb-treated mice revealed that antibody treatment resulted in the elimination of greater than 98% of L3T4+ T cells, but had no effect on the Lyt-2+ T cells subset. Tumor regression was immunologically mediated, because L5178Y lymphoma cells were shown to be L3T4-, and regression of the tumor failed to occur in mice that had been lethally irradiated before anti-L3T4 mAb was given. Tumor regression was mediated by tumor-sensitized Lyt2+ T cells, as evidenced by the finding that treatment of tumor-bearing mice with anti-Lyt-2 mAb alone, or in combination with anti-L3T4 mAb, resulted in enhancement of tumor growth and a significant decrease in host survival time. Moreover, the spleens of mice whose tumors were undergoing regression in response to anti-L3T4 mAb treatment contained Lyt-2+ T cells capable, on passive transfer, of causing regression of a tumor in recipient mice. These results can be interpreted as showing that removal of tumor-induced L3T4+ suppressor T cells results in the release of Lyt-2+ effector T cells from suppression, and consequently in the generation of enough Lyt-2+ T cell-mediated immunity to cause tumor regression. This can only be achieved, however, if immunity to the tumor is mediated exclusively by Lyt-2+ T cells, as is the case for the L5178Y lymphoma. In the case of the P815 mastocytoma, treatment with anti-L3T4 mAb was without a therapeutic effect, and this was in keeping with the finding that immunity to this tumor is mediated by L3T4+, as well by Lyt-2+ T cells.

Generation of CD8 T Cell-Mediated Protective Immunity against Tumor Escapees

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2623-2623 ◽  
Author(s):  
Bindu Varghese ◽  
Behnaz Taidi ◽  
Adam Widman ◽  
James Do ◽  
R. Levy
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Cd8 T Cell

Abstract Introduction: Anti-idiotype antibodies against B cell lymphoma have shown remarkable success in causing tumor regression in the clinic. In addition to their known ability to mediate ADCC, anti-idiotype antibodies have also been shown to directly inhibit the proliferation of tumor cells by sending negative growth signals via the target idiotype. However, further studies to investigate this mechanism have been hindered by the failure of patient tumor cells to grow ex vivo. Methods and Results: In order to study this phenomenon further, we developed an antibody against the idiotype on an A20 mouse B lymphoma cell line. A radioactive thymidine incorporation assay showed decreased A20 cell proliferation in the presence of the anti-id antibody ex vivo. In vivo, when mice were treated intraperitoneally (i.p.) with 100 μg of antibody 3 hours post-tumor inoculation (1×106 A20 subcutaneously (s.c.)), tumor growth was delayed for greater than 40 days after which the tumor began to grow once again. Further analysis of these escaping tumor cells by flow cytometry showed that that the tumor cells escaped the antibody-mediated immune response by down-regulating expression of idiotype and IgG on their surfaces although the cells retained idiotype expression intracellularly. This down-regulation of surface idiotype rendered the tumor cells resistant to both ADCC and signaling-induced cell death. The addition of an immunostimulatory bacterial mimic (CpG-DNA; 100 μg × 5 intratumoral (i.t.) injections; Days 2, 3 4, 6 & 8) to antibody therapy (Day 0; 100 μg i.p.) cured large established tumors (Day 0 = 1 cm2) and prevented the occurrence of tumor escapees (p<0.0001). Antibody plus CpG combination therapy in tumor-bearing mice deficient for CD8+ T cells demonstrated the critical role of CD8+ T cells in A20 tumor eradication (p<0.005). Depletion of CD4+ T cells was found to have no significant impact on the therapy. We also found that when mice were inoculated with two tumors and treated with anti-idiotype antibody (i.p.) followed by intratumoral CpG in just one tumor (Day 0=1 cm2; anti-idiotype antibody 100 μg Day 0; 100 μg CpG Days 2, 3, 4, 6 & 8), untreated tumors regressed just as well as CpG-treated tumors indicating a systemic anti-tumor immune response was generated. Conclusion: Anti-idiotype therapy, although effective in delaying tumor growth, frequently generates antigen-loss variants. However, we found that when anti-idiotype antibodies were combined with CpG, even large established tumors were cured due to systemic CD8+ T cell-dependent tumor immunity. Rather than simply mediating ADCC against a single tumor antigen, which requires the constant infusion of antibody to hamper tumor growth, we hypothesize a cytotoxic T-cell response against many tumor antigens was also generated. Such a diverse T-cell repertoire can prevent the emergence of tumor escapees and collectively provide long-lasting tumor protection. These pre-clinical results suggest that anti-tumor antibodies combined with CpG warrant further study in patients with B cell lymphoma.

scholarly journals The immunological basis of endotoxin-induced tumor regression. Requirement for T-cell-mediated immunity.

1978 ◽  
Vol 148 (6) ◽  
pp. 1550-1559 ◽  
Author(s):  
M J Berendt ◽  
R J North ◽  
D P Kirstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Gamma Irradiation ◽  
Tumor Regression ◽  
Whole Body ◽  
Cell Mediated Immunity ◽  
Complete Regression ◽  
Murine Tumors ◽  
Hemorrhagic Necrosis

It was shown that although intravenous administration of bacterial endotoxin caused extensive hemorrhagic necrosis of four different syngeneic murine tumors, only two of these tumors subsequently underwent complete regression: the two that were shown to be immunogeneic as classically defined. An immunologic basis for endotoxin-induced regression was further indicated by the additional findings that regression, but not hemorrhagic necrosis, of the two immunogenic tumors failed to occur in mice that were immunodepressed by whole-body gamma-irradiation, or that were made T-cell deficient by thymectomy and irradiation. That endotoxin-induced regression is T-cell mediated was suggested by the findings that tumor regression was followed by a state of long-lived immunity to a tumor cell challenge implant, and with the possession by the host of T cells that were capable of passively transferring this state of immunity to normal recipients. It is concluded that although parenteral injection of endotoxin causes hemorrhagic necrosis of most solid murine tumors, it is only those tumors that are immunogenic enough to evoke the generation of T-cell-mediated immunity which subsequently go on to completely regress.

Lenalidomide Synergistically Enhances the Effect of Dendritic Cell Vaccination in Mouse Multiple Myeloma Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5010-5010
Author(s):  
Thanh-Nhan Nguyen-Pham ◽  
Sung-Hoon Jung ◽  
Manh-cuong Vo ◽  
Hyun Ju Lee ◽  
My-Dung Hoang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Innate Immune ◽  
Effector Memory ◽  
Dendritic Cell Vaccination ◽  
Dc Vaccine ◽  
And Function

Abstract Abstract 5010 Background: Multiple myeloma (MM) is a B-cell malignancy that has remained essentially incurable by conventional therapy, highlighting the urgent need for novel treatment strategies. Lenalidomide (LEN) is thalidomide analog belonging to the class of immunomodulatory drugs which the activity are related with immunomodulatory properties. LEN augments both the adaptive and innate immune system via the co-stimulation of T cells, NK and NKT cells. In addition, LEN can inhibit the frequency and function of immunosuppressor cells. Therefore, LEN could be used to enhance immune response against MM. Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic modality to treat MM. The purpose of this study was to investigate the immunomodulatory effects of lenalidomide in combination with DCs vaccine to treat MM in vivomouse model. Methods: We used the MOPC315 myeloma murin model to evaluate tumor-specific cytotoxic T lymphocytes responses by a DC vaccine in combination with LEN. After tumor growth, LEN (50 mg/kg/day) was injected intraperitoneally at three consecutive days to cover the DC vaccination. The tumor growth inhibition effect and the antitumor activity of splenocytes from vaccinated mice were evaluated to reveal the synergistic effect of DCs and LEN. Results: The combination of LEN and DC vaccine efficiently inhibited tumor growth in mouse MM model when compared to single therapeutic agent. These vaccinated mice exhibit the reduction of myeloid-derived suppressor cells (MDSC) and regulatory T cell (Treg) in spleen. Inhibition of MDSC and Treg resulted in the increasing proportion of CD4+ and CD8+T cell in the spleen. High ratio of Th1- to Th2-type cytokines was induced by LEN plus DC vaccine. LEN also enhance the innate immune response by modulating NK cell number and function. In addition, LEN also can enhance the population of effector memory T cells in the spleen of vaccinated mice. Furthermore, the treatment of LEN can down-regulate the levels of VEGF and TNF-a on tumor tissues of vaccinated mice. Conclusion: These results suggest that a treatment combining the immunomodulatory drug lenalidomide with DC vaccine can improve antitumor immunity in mouse MM model by inhibiting immunosuppressor cells and recovering effector cells, as well as superior polarization of the Th1/Th2 balance in favor of Th1 type immune response. Disclosures: No relevant conflicts of interest to declare.

C5a Complement Depletion Suppresses In Vivo B Lymphoma Progression and Enhances Development Of Cellular Anti-Tumor Immune Response

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1837-1837
Author(s):  
Suresh Veeramani ◽  
George J. Weiner
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cd8 T Cells ◽  
B Lymphoma

Abstract Background Proteins within the complement system have complex effects on cellular immune responses. In previous studies, we found that active complement components, especially C5a, can dampen the development of antigen-specific immune responses following vaccination with a model antigen, in part by promoting generation of APC-induced T regulatory (Treg) cells. These studies also demonstrated that B lymphoma cell lines exposed to complement can induce Treg generation in vitro. The current study was designed to address whether depletion of C5a could enhance development of a cellular anti-lymphoma immune response in vivo. Methods Immunocompetent Balb/C mice were inoculated subcutaneously with syngeneic A20 B lymphoma cells mixed with either 10 μg of rat anti-mouse C5a monoclonal antibody (mAb) or 10 μg of isotype-matched Rat IgG2a control mAb. Tumor growth was followed. In select experiments, mice were sacrificed and analyzed for the percentage and activity of tumor-infiltrating T cells and A20-specific splenic T cell responses. Results 1. Tumor progression. Lymphoma grew more slowly in mice treated with anti-C5a mAb compared to mice treated with control mAb (p<0.05) {Fig. 1). 2. Intratumoral T cells. Tumors from mice treated with anti-C5a mAb had higher CD8+ T cell infiltration compared to mice treated with control mAb (p=0.002) (Fig. 2). Tumor-infiltrating CD8+ T cells showed a trend towards higher intracellular IFNg production in mice treated with anti-C5a mAb compared to control mAb (p=0.051). 3. Splenic T cells. Splenic T cells from mice treated with anti-C5a mAb produced IFNg to a greater degree than did splenic T cells from control mice when splenocytes were cultured with irradiated A20 cells in vitro (p=0.041) (Fig. 3). There was a trend towards decreased numbers of splenic CD4+CD25highFoxp3+ Tregs in C5a-depleted mice compared to control mice. Conclusions Depletion of C5a at the site of tumor inoculation slows tumor growth and increases the number of tumor infiltrating CD8 T cells in a syngenic immunocompetent model of lymphoma. A trend towards enhanced production of IFNg in the tumor infiltrating T cells, increased numbers of tumor-specific splenic T cells, and reduced numbers of splenic Tregs, suggests intratumoral C5a depletion can enhance tumor-specific immune responses both within the tumor and systemically. Ongoing studies are exploring the molecular mechanisms involved in C5a-promoted tumor progression and the use of C5a depletion as a novel strategy to improve anti-tumor immunity. Disclosures: No relevant conflicts of interest to declare.

scholarly journals AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Stephen M. Shaw ◽  
Jenny Middleton ◽  
Kim Wigglesworth ◽  
Amber Charlemagne ◽  
Oliver Schulz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Tumor Antigen ◽  
Tumor Regression ◽  
Antigen Uptake

Abstract Background Treatments that generate T cell-mediated immunity to a patient’s unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galα1-3Galβ1-4GlcNAc (α-Gal) in situ leading to opsonization with pre-existing natural anti-α-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity. Methods Various immunological effects of coating tumor cells with α-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (α1,3GT−/−) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel–Cox test, C5a data by Mann–Whitney test, and single tumor regression by repeated measures analysis. Results In vitro, α-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8α+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in α1,3GT−/− mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth. Conclusions We have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment.

scholarly journals IL-7 coupled with IL-12 increases intratumoral T cell clonality, leading to complete regression of non-immunogenic tumors

2021 ◽  
Author(s):  
Mamoru Tasaki ◽  
Midori Yamashita ◽  
Yukinori Arai ◽  
Takafumi Nakamura ◽  
Shinsuke Nakao
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Frequency ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Receptor ◽  
Complete Regression ◽  
Tcr Repertoire ◽  
Clinical Benefits

AbstractImmune checkpoint inhibitors against PD-1, PD-L1 and CTLA-4 have altered the treatment paradigm for various types of cancers in the past decade. However, they offer clinical benefits to only a subset of patients. Evaluation and identification of an appropriate therapeutic approach to improve intratumoral immune status are needed for better treatment outcomes. We previously demonstrated that intratumoral expression of IL-7 and IL-12 increased tumor-infiltrating lymphocytes in poorly immunogenic tumors, resulting in a higher tumor regression rate than IL-12 alone. However, the mechanism underlying the difference in efficacy with and without IL-7 remains unclear. Here, we identified a previously unknown effect of IL-7 on the T cell receptor (TCR) repertoire of intratumoral CD8+ T cells, which is induced in the presence of IL-12. While IL-7 alone increased the diversity of intratumoral CD8+ T cells, IL-7 with IL-12 increased a limited number of high-frequency clones, conversely augmenting IL-12 function to increase the clonality. The proportion of mice with multiple high-frequency clones in tumors correlated with that achieving complete tumor regression in efficacy studies. These findings provide a scientific rationale for combining IL-7 and IL-12 in anticancer immunotherapy and unveil a novel IL-7 function on intratumoral TCR repertoire.

scholarly journals 768 Systemic delivery of a tumor-targeted TLR9 agonist conjugate transforms the tumor immune landscape and induces tumor regression in mice

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A803-A803
Author(s):  
Caitlyn Miller Candidate ◽  
Idit Sagiv-Barfi ◽  
Patrick Neuhoefer ◽  
Debra Czerwinski ◽  
Steven Artandi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tumor Targeting ◽  
Tumor Regression ◽  
Breast Tumors ◽  
Live Cells ◽  
Systemic Delivery ◽  
Tlr9 Agonist

BackgroundTumor-localized delivery of Toll-like receptor (TLR) agonists is a promising strategy to promote immune activation within the tumor microenvironment (TME) to overcome tumor immunosuppression and induce anti-tumor immune responses. To enable localization to multiple tumor sites following systemic administration, we developed a fully-synthetic tumor-targeting TLR9 agonist and demonstrate its potential to transform the tumor immune microenvironment for effective tumor regression in mice.MethodsAn engineered synthetic peptide (PIP) that binds to multiple integrin receptors overexpressed in many solid tumors was chemically conjugated to a synthetic CpG oligonucleotide (TLR9 agonist), thereby generating a tumor-targeting immune-stimulant referred to as PIP-CpG. To facilitate clinical translation, PIP-CpG is cross-reactive between mouse, non-human primate, and human. Therapeutic studies were conducted in immune-competent mice bearing breast or pancreatic tumors to evaluate the efficacy of intravenously (IV)-injected PIP-CpG compared to IV-injected unmodified CpG or vehicle (PBS). We then performed mechanistic studies to evaluate the immune response elicited by PIP-CpG therapy.ResultsIntravenous dosing of PIP-CpG led to tumor regression and prolonged survival, and in some cases cures, relative to vehicle or unmodified CpG therapy in both murine breast (4T1) and pancreatic cancer (KPC-G2) models. This tumor regression was dependent on T cells as T cell depletion resulted in loss of therapeutic response. To study the effect of systemic therapy on the cellular landscape in the TME, we analyzed 4T1 breast tumors by flow cytometry. We found that vehicle and CpG IV-dosed mice had immunosuppressive TMEs comprised mostly of myeloid-derived suppressor cells (MDSCs; 43–68% of live cells) with minimal infiltrating T cells and B cells (5–16% of live cells). In contrast, the TME of PIP-CpG treated mice was transformed into a lymphocyte-rich “hot” tumor phenotype with massive infiltration by T cells and B cells (92–95% of live cells) and plummeting levels of MDSCs (down to ~1%). In addition, tumor-specific effector CD8+ T cells were generated in response to PIP-CpG therapy, but not CpG dosed IV, indicating that PIP-CpG therapy transforms the TME and elicits a T cell-mediated tumor-specific immune response. Furthermore, PIP-CpG was effective for treating MMTV-PyMT transgenic mice, which spontaneously develop multiple breast tumors. Murine toxicity studies indicated that effects of PIP-CpG were similar to CpG dosed IV or intratumorally, which have been well-tolerated in human clinical trials.ConclusionsTumor-directed systemic delivery of a TLR9 agonist transforms the TME via activated B and T cells and is promising for further development in patients with solid tumors.Ethics ApprovalAll mouse experiments were performed in accordance with protocols approved by the Stanford Administrative Panel on Laboratory Animal Care.

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