Immunotherapy Abstracts 1

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The immunoinhibitory B7-H1 molecule as a potential target in cancer: killing many birds with one stone.
            (Afreen and Dermime, 2014) Download
Over expression of B7-H1 (also named PDL-1 or CD 274) molecule in cancer has been linked to worse prognosis and resistance to anti-cancer therapies in several malignancies. In this review, we update on the expression of B7-H1 molecule in solid and hematological malignancies. We also describe the possible mechanisms by which this molecule inhibits/downregulates the immune response to cancer cells. Finally, we highlight current and future potential therapeutic strategies that can be further developed to target this molecule.

Tumor-associated bacteria capable of producing a human choriogonadotropin-like substance.
            (Backus and Affronti, 1981) Download
Aerobic microorganisms were isolated and identified from 9 of 10 malignant tissues aseptically obtained from surgical patients. The organisms isolated are species commonly associated with the flora of the human body. When these cancer-associated organisms were grown in Trypticase soy broth (BBL Microbiology Systems), a protein substance was isolated from the culture filtrates by acetone precipitation. The acetone precipitates of 12 of 14 organisms tested were positive when assayed by radioimmunoassay for the beta subunit of human chorionic gonadotropin (hCG). All but one of the bacterial isolates from the malignancies were capable of producing the hCG-like substance, but in varying quantities. Control organisms (not isolated from a malignancy) and uninoculated Trypticase soy broth were either completely negative in the radioimmunoassay for beta hCG or had levels of beta hCG near the limit of the sensitivity of the method. These results suggest the possibility that bacteria-tumor relationships do exist and are in agreement with the findings of other workers. Investigation of these relationships may have important and provocative implications in the study of neoplastic diseases.


 

Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro.
            (Blank et al., 2006) Download
Human tumors frequently escape immune destruction, despite the presence of cytotoxic T cells (CTL) recognizing tumor-associated antigens (TAA). We have previously shown that programmed death ligand-1 (PD-L1), a recently identified ligand of the B7 superfamily, is expressed on murine tumors and can inhibit antitumor immune responses. To evaluate the clinical relevance of our animal model findings, we examined human tumors and tumor-specific T cells. We found PD-L1 to be constitutively expressed on human renal cell carcinoma (RCC) cell lines and upregulated on human melanoma cell lines upon exposure to interferon-gamma. Similarly, we found binding of anti-PD-L1 monoclonal antibody (mAb) on frozen sections from RCC and melanomas, but not on normal tissues. The corresponding inhibitory receptor of PD-L1, PD-1, revealed a higher expression on tumor-infiltrating lymphocytes than on peripheral blood lymphocytes (PBL) from melanoma patients upon specific antigen stimulation. Stimulation of PBL from healthy donors with peptide-loaded dendritic cells in the presence of anti-PD-L1 mAb altered neither the total T cell numbers after expansion, nor the percentage of peptide-specific CTL, when providing a T cell help by addition of cytokines. However, when stimulating TAA-specific CTL and T helper cells with Ag-pulsed dendritic cells in the absence of exogenous cytokines, PD-L1 blockade increased the cytokine production. Similar to the data achieved in the murine system, the blockade of PD-L1 on human tumors resulted in enhanced cytolytic activity of TAA-specific CTLs and cytokine production of TAA-specific T helper cells when interacting directly with the tumor. In summary, our data suggest that PD-L1/PD-1 interactions negatively regulate T cell effector functions predominantly in the absence of exogenous cytokine support, indicating an important role for this pathway in tumor evasion.

Immunotherapy for the prevention and treatment of type 1 diabetes: optimizing the path from bench to bedside.
            (Bresson and von Herrath, 2009) Download
Realizing immune-based interventions for human type 1 diabetes will be necessary, even if an unlimited source of new islets can be obtained from stem cells or other sources, because autoimmune memory cells will have to be controlled to avoid continued loss of  beta cells over time. The key issue that must be tackled is achieving a toler- able balance between immunosuppres- sion and the associated side-effects and long-term tolerance.


 

Blocking tumor escape in hematologic malignancies: the anti-PD-1 strategy.
            (Bryan and Gordon, 2015) Download
Immunotherapy remains an important tool for treatment of hematologic malignancies. The Programmed Death-1 (PD-1) immune checkpoint pathway has emerged as a mechanism of tumor evasion from the anti-tumor immune response. The recent development of anti-PD-1 monoclonal antibodies has offered a targeted approach to cancer therapy. Several agents are in various stages of development and have shown clinical responses across a broad spectrum of both solid and hematologic malignancies. The use of anti-PD-1 therapy in hematologic malignancies is limited but has demonstrated clinical responses in relapsed/refractory disease following multiple lines of therapy. PD-1 blockade may reduce relapse rates for patients who fail to obtain a complete remission prior to autologous hematopoietic cell transplant. The role of the PD-1 pathway for tumor escape is reviewed. We explore the use of anti-PD-1 therapy in hematologic malignancies. The proposed mechanism of PD-1 blockade as a modulator of the innate and acquired immune response is considered. Finally, the challenges of anti-PD-1 therapy and the future direction of investigation in this area are reviewed.

Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity.
            (Carmi et al., 2015) Download
Whereas cancers grow within host tissues and evade host immunity through immune-editing and immunosuppression, tumours are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumours are reliably rejected by host T cells, even when the tumour and host share the same major histocompatibility complex alleles, the most potent determinants of transplant rejection. How such tumour-eradicating immunity is initiated remains unknown, although elucidating this process could provide the basis for inducing similar responses against naturally arising tumours. Here we find that allogeneic tumour rejection is initiated in mice by naturally occurring tumour-binding IgG antibodies, which enable dendritic cells (DCs) to internalize tumour antigens and subsequently activate tumour-reactive T cells. We exploited this mechanism to treat autologous and autochthonous tumours successfully. Either systemic administration of DCs loaded with allogeneic-IgG-coated tumour cells or intratumoral injection of allogeneic IgG in combination with DC stimuli induced potent T-cell-mediated antitumour immune responses, resulting in tumour eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumours and metastases, as well as the injected primary tumours. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumour antigens after culture with allogeneic-IgG-loaded DCs, recapitulating our findings in mice. These results reveal that tumour-binding allogeneic IgG can induce powerful antitumour immunity that can be exploited for cancer immunotherapy.

Tumor-binding antibodies and tumor immunity.
            (Carmi and Engleman, 2015) Download
Taken together, these findings show that the impact of tumor- binding IgG on tumor growth is context dependent. In an immunostimulatory milieu, such antibodies can induce powerful anti-tumor immunity that can potentially be harnessed for the treatment of patients with cancer.

Immunotherapy on trial for new-onset type 1 diabetes.
            (Faustman, 2008) Download
In this issue of the Journal, Ludvigsson et al.8 describe a randomized, controlled clinical trial in- volving children with new-onset type 1 diabetes to examine the safety and efficacy of immuno- therapy with the recombinant human 65-kD iso- form of glutamic acid decarboxylase (GAD) in a standard vaccine formulation with alum (GAD- alum) (ClinicalTrials.gov number, NCT00435981).

PD-1 and its ligands in tolerance and immunity.
            (Keir et al., 2008) Download
Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.


Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy.
            (Kranz et al., 2016) Download
Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.

PD-L2 is a second ligand for PD-1 and inhibits T cell activation.
            (Latchman et al., 2001) Download
Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.

The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma.
            (Mahoney et al., 2015) Download
PURPOSE:  Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. METHODS:  PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. FINDINGS:  The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. IMPLICATIONS:  This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer.
            (Quezada and Peggs, 2013) Download
The past few years have witnessed something of a renaissance in the field of cancer immunotherapy, relating largely to the clinical advances that have been associated with the development of monoclonal antibodies targeting the immune inhibitory co-receptors CTLA-4 and PD-1 and to the pursuit of genetically modified antigen-redirected adoptive T-cell therapies. These advances are based on a more substantial understanding of the factors restricting effective immune therapies that has been derived from the study of pre-clinical models of tumour growth in immune competent mice. Just as the recognition of the importance of positive co-stimulatory signaling has been instrumental to recent advances in the development of genetically modified antigen-specific adoptive cellular therapies, an increasing awareness of the ability of tumours to subvert multiple immune inhibitory pathways, effectively blunting the development or expansion of any anti-tumour immunity, is fostering the development of novel therapies that appear active as monotherapies but may achieve their greatest impact in combinatorial regimens. This mini-review will focus on attempts to target co-inhibitory members of the immunoglobulin superfamily.

Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future.
            (Rewers and Gottlieb, 2009) Download
Bresson and von Herrath (1) reviews basic mechanisms underlying immunoprevention and immunotherapy of type 1 diabetes as well as selected human trials in the context of data from animal models.

Programmed death 1 pathway inhibition in metastatic renal cell cancer and prostate cancer.
            (Tang and Heng, 2013) Download
Programmed death 1 (PD-1) is a T cell co-inhibitory receptor with two ligands, PD-L1 and PD-L2. In cancer, this pathway plays a major role in immune resistance in the tumor environment. Blockade of this pathway can enhance antitumor immune responses. This review discusses the preclinical rationale for PD-1 pathway inhibition in advanced renal cell carcinoma and prostate cancer, in addition to the clinical activity and toxicity of the anti-PD-L1 antibody BMS-936559, as well as anti-PD-1 antibodies MK-3475 and BMS-936558.


 

Expression of costimulatory molecules on human retinoblastoma cells Y-79: functional expression of CD40 and B7H1.
            (Usui et al., 2006) Download
PURPOSE:  To examine the expression of various costimulatory molecules on the human retinoblastoma cell line Y-79 and assess the functional roles of selected costimulatory molecules. METHODS:  Y-79 cells were incubated in the presence or absence of IFN-gamma, with or without irradiation (100 Gy). Expression of major histocompatibility complex (MHC) class I molecules, MHC class II, CD80, CD86, CD40, CD70, B7H1, B7DC, B7H2, OX40L, and 4-1BBL on Y-79 cells was measured by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometric analysis. The functional role of CD40-mediated interactions in modifying immune responses to Y-79 was assessed in vitro by using recombinant human CD40 ligand (rhCD40L). The costimulatory effect of B7H1-expressing IFN-gamma-treated Y-79 cells on proliferation of purified T cells was studied in Y-79/T-cell coculture experiments with a blocking anti-B7H1 monoclonal antibody (mAb). RESULTS:  CD40 and B7H2 were consistently detected on Y-79 cells by RT-PCR and flow cytometry. Cell surface expression of CD40 was upregulated on stimulation by IFN-gamma alone, radiation alone, and IFN-gamma combined with radiation. B7H1 expression was induced by IFN-gamma stimulation and increased further when irradiated Y-79 cells were stimulated by IFN-gamma. Treatment of Y-79 cells with rhCD40L enhanced cell surface expression of MHC class I and intercellular adhesion molecule (ICAM)-1 and also stimulated monocyte chemotactic protein (MCP)-1 production. Proliferative response of purified CD3+ T cells costimulated with IFN-gamma-stimulated Y-79 was significantly enhanced by the addition of anti-B7H1 mAb. CONCLUSIONS:  These results suggest that CD40 expressed on Y-79 plays an important role in augmenting antitumor immunity. In contrast, the expression of B7H1 on IFN-gamma-treated Y-79 cells contributes to the suppression of T cells. The dual effects of CD40 and B7H1 on Y-79 cells may contribute to positive or negative regulation of antitumor immune responses in human retinoblastoma.

Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis.
            (Wintterle et al., 2003) Download
Human glioblastoma is a highly lethal tumor that is known for its immune inhibitory capabilities. B7-homologue 1 (B7-H1), a recently identified homologue of B7.1/2 (CD80/86), has been described to exert costimulatory and immune regulatory functions. We investigated the expression and the functional activity of B7-H1 in human glioma cells in vitro and in vivo. Although lacking B7.1/2 (CD80/86), all 12 glioma cell lines constitutively expressed B7-H1 mRNA and protein. Exposure to IFN-gamma strongly enhanced B7-H1 expression. Immunohistochemical analysis of malignant glioma specimens revealed strong B7-H1 expression in all 10 samples examined, whereas no B7-H1 expression could be detected on normal brain tissues. To elucidate the functional significance of glioma cell-related B7-H1 expression, we performed coculture experiments of glioma cells with alloreactive CD4+ and CD8+ T cells. Glioma-related B7-H1 was identified as a strong inhibitor of CD4+ as well as CD8+ T-cell activation as assessed by increased cytokine production (IFN-gamma, interleukin-2, and interleukin-10) and expression levels of the T-cell activation marker (CD69) in the presence of a neutralizing antibody against B7-H1 (mAb 5H1). B7-H1 expression may thus significantly influence the outcome of T-cell tumor cell interactions and represents a novel mechanism by which glioma cells evade immune recognition and destruction.

Cancer: Antitumour immunity gets a boost.
            (Wolchok and Chan, 2014) Download
Five papers extend the list of cancers that respond to therapies that restore antitumour immunity by blocking the PD-1 pathway, and characterize those patients who respond best.

B7-H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells.
            (Yao et al., 2009) Download
Human glioblastoma is well known for its capacity to interfere with effective antitumor immune responses. B7-H1 is the third member of the B7 family that plays important roles in tumor immune evasion. Recent studies have shown that brain tumor stem-like cells (TSCs) contribute to tumorigenesis and radioresistance. However, the relationship between B7-H1 and the clinical behavior of brain TSCs remains unclear. In the present study, we report that B7-H1 is correlated with the malignancy grade of astrocyte tumors. B7-H1 was significantly upregulated at the growing edge of the tumors. Immunostaining and flow cytometric analysis indicate that B7-H1 was expressed primarily by Ki67-negative tumor cells. In vitro, tumors cultured under medium favoring the growth of neural stem cells were able to form spheres, along with expression of neural stem/progenitor cell markers. These cells were able to differentiate into different neural lineages when cultured in differentiation medium, indicating that these cells have TSC characteristics. We also found that B7-H1 was expressed, but not exclusively on CD133-positive stem cells. Interestingly, we found that CD133-negative tumor cells also had the capacity to form brain tumors. Our data establish a correlation between the expression of the negative costimulatory molecule B7-H1 and the malignancy grade of human gliomas, suggesting that B7-H1 may be a novel tumor marker and target for therapy, although it is not expressed exclusively on brain TSCs.


 

References

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Bresson, D and M von Herrath (2009), ‘Immunotherapy for the prevention and treatment of type 1 diabetes: optimizing the path from bench to bedside.’, Diabetes Care, 32 (10), 1753-68. PubMed: 19794001
Bryan, LJ and LI Gordon (2015), ‘Blocking tumor escape in hematologic malignancies: the anti-PD-1 strategy.’, Blood Rev, 29 (1), 25-32. PubMed: 25260226
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Mahoney, KM, GJ Freeman, and DF McDermott (2015), ‘The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma.’, Clin Ther, 37 (4), 764-82. PubMed: 25823918
Quezada, SA and KS Peggs (2013), ‘Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer.’, Br J Cancer, 108 (8), 1560-65. PubMed: 23511566
Rewers, M and P Gottlieb (2009), ‘Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future.’, Diabetes Care, 32 (10), 1769-82. PubMed: 19794002
Tang, PA and DY Heng (2013), ‘Programmed death 1 pathway inhibition in metastatic renal cell cancer and prostate cancer.’, Curr Oncol Rep, 15 (2), 98-104. PubMed: 23263823
Usui, Y, et al. (2006), ‘Expression of costimulatory molecules on human retinoblastoma cells Y-79: functional expression of CD40 and B7H1.’, Invest Ophthalmol Vis Sci, 47 (10), 4607-13. PubMed: 17003458
Wintterle, S, et al. (2003), ‘Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis.’, Cancer Res, 63 (21), 7462-67. PubMed: 14612546
Wolchok, JD and TA Chan (2014), ‘Cancer: Antitumour immunity gets a boost.’, Nature, 515 (7528), 496-98. PubMed: 25428495
Yao, Y, et al. (2009), ‘B7-H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells.’, Neuro Oncol, 11 (6), 757-66. PubMed: 19264916