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Two human anti-CD antibodies, binding to the extracellular domain of CD, urelumab and utomilumab are currently undergoing clinical testing. Urelumab has shown several single-agent, partial responses, but its use has been hampered by hepatoxicity, whilst utomilumab has shown little or no single agent activity. Their small size 1. We hypothesised that a fully synthetic Bicycle CD agonist with rapid renal clearance, minimal liver interaction and no Fc receptor interaction may induce CD mediated anti-tumour activity while avoiding liver toxicity.

BCY binds to the human CD ligand-binding site. In common with many TNF receptors, CD activation requires receptor crosslinking, thus multivalent binders would be expected to recapitulate the action of its natural trimeric ligand. We developed molecules exhibiting a wide range of potency in a cell-based CDdependent reporter assay. In addition, these molecules activate human T cells in vitro as monitored by increased cytokine release. Selected CD multimers are being tested in a humanized CD mouse model to demonstrate T cell activation and anti-tumour activity, without the liver toxicity reported for urelumab.

We hypothesise that such molecules could be promising, novel cancer immunotherapy candidates and importantly, they pave the way for development of synthetic agonists of other TNF receptors. Preclinical and ongoing clinical studies support the application of TLR9 agonists for immunotherapy. Lefitolimod activates plasmacytoid dendritic cells to secrete interferon-alpha, followed by a broad activation of cells of the innate and adaptive immune system.

Lefitolimod therefore provides the necessary and sufficient signals for the initiation of an immunotherapeutic anti-tumor response. It was evaluated, if lefitolimod is able to induce local and systemic anti-tumor immune responses in the murine syngeneic colon carcinoma CT26 and the breast cancer EMT-6 models. This beneficial TME modulation and antigen-specific effects were associated with a markedly reduced tumor growth in the CT26 model. The anti-tumor effect was even more pronounced in the EMT-6 model, where nine out of ten mice showed complete tumor regression.

This indicates that treatment with lefitolimod induces a sustained, long-lasting immune memory against shared antigens of both tumor types. Treatment of tumors with lefitolimod resulted in a beneficial modulation of the TME with an increase in anti-tumor effector cells.

A strong systemic immune response as well as a sustained immune memory against different tumors was induced. These data indicate that lefitolimod provides the essential requirements for use as mono- immunotherapy or as an optimal combination partner of other immunotherapeutic drugs like checkpoint inhibitors in immuno-oncological trials. Novel therapeutic proteins which confer T cell costimulation may be particularly effective anti-tumor therapies, particularly in combination with checkpoint inhibitors.

But at the same time, localization of such costimulatory activity to tumors, such as via a tumor-specific targeting antigen, may be simultaneously important to maintain tolerability of such agonist therapeutics. B7-H6, a cell surface immunoglobulin superfamily IgSF member which binds the NKp30 receptor, appears to be expressed specifically in multiple tumor types, and may serve as such a tumor-specific antigen.

Novel therapeutic proteins which localize costimulatory agonist domains to B7 H6 may therefore be capable of significant antitumor efficacy yet may be safely administered systemically by preferentially localizing agonist activity to the B7-H6 tumor microenvironment. These findings further suggest tumor-localized immunomodulation is possible and may improve cancer outcomes. All animal procedures were approved by the appropriate Institutional Animal Care and Use Committee overseeing the vivarium where the studies were conducted Alpine Immune Sciences and Charles River Laboratories , and followed the guidelines set forth in the 8th Edition of the Guide for the Care and Use of Laboratory Animals National Research Council, Background: The success of immunotherapeutic checkpoint blockade in cancer has led to great interest in finding novel targets that play a pivotal role in immune responses.

Samples were also subjected to high parameter mass-spec based flow cytometry and both mutational and transcriptional profiling by deep sequencing and clinical parameters age, sex, blast count, ELN risk stratification were recorded. Results: Of 57 total samples tested, 24 Immune checkpoint inhibitor antibodies that can re- activate anti-tumor immunity show great promise for the treatment of cancer. Similarly, therapeutic agents that boost anti-tumor immunity by direct activation of immunostimulatory molecules may provide clinical benefit.

In this context, targeting tumor necrosis factor TNF receptor superfamily members, which deliver essential co-stimulatory activity for immune responses, gained attention. We hypothesized that simultaneous engagement of the T-cell co-stimulatory molecule BB and CD40 on antigen-presenting cells APCs using a bispecific antibody could be an elegant and potent mechanism to induce conditional activation of both CDpositive immune cells and BB positive T cells.

The binding characteristics and functional activity of DuoBody-CD40xBB were analyzed in vitro using flow cytometry, cell-based reporter assay systems and primary human lymphocyte assays. To evaluate the capacity of DuoBody-CD40xBB to induce proliferation of tumor-infiltrating lymphocytes TILs in the tumor microenvironment, ex vivo TIL expansion assays were conducted using freshly isolated human tumor specimen. The monospecific control antibodies did not show agonist activity.

This demonstrates that the bispecific antibody confers conditional activity upon receptor cross-linking. Using human primary T cells and monocyte-derived dendritic cells, both obtained from human healthy donor PBMCs, antigen-specific T-cell assays were conducted in vitro. Furthermore, in ex vivo cultures of fresh human tumor tissue resections DuoBody-CD40xBB increased the expansion of TILs up to fold over control antibody treatment. In summary, DuoBody-CD40xBB is a bispecific antibody that crosslinks CD40 and BB positive cells, thereby inducing conditional stimulation and subsequently co-stimulatory activity.

In the context of cancer, DuoBody-CD40xBB can enhance anti-tumor immunity by re- activating tumor-specific T cells, either intratumorally or in the tumor-draining lymph nodes. To fully exploit these mechanisms may require the mAb to be dosed at levels that provide significant tumor and tissue penetration, without dose-limiting-toxicities DLT from systemic CD40 activation.

Our agonist CD40 mAb, CDX, was selected based on its unique and linear dose-dependent in vitro and in vivo activity and is postulated will achieve maximum agonist activity at dose levels associated with good systemic exposure. In toxicology studies, CDX demonstrated potent CDmediated pharmacological effects without significant toxicities.

The primary endpoint is determining the safety profile and maximum tolerated dose. Secondary endpoints include pharmacokinetics, immunogenicity, clinical and biological outcome assessments. Baseline and on-study biopsies will be used to explore the pharmacodynamic effects of CDX in the tumor microenvironment TME.

Tumor-specific expansion cohorts will further explore the activity of CDX To date, CDX cohorts at 0. Expected pharmacodynamic effects, including transient, dose-dependent decreases in lymphocyte counts and dose-dependent increases in serum ILp40 and TNF-Alpha, have been observed. The early data suggest that CDX has the expected immune activating and safety profile.

Multiple studies have demonstrated that tumors establish an immunosuppressive microenvironment TME to escape immune surveillance and promote tumor development. Tumor-infiltrating lymphocytes TILs become suppressed in the TME so their proliferative capacity and effector functions are impaired.

In multiple syngeneic mouse tumor models, treatment with GITR agonists demonstrates compelling anti-tumor activity. Based on these promising preclinical data, a number of GITR agonist agents are being tested in the clinic.

PTZ has agonistic activity in engineered cell assays and primary T cells from peripheral blood of healthy donors. Moreover, this activity was observed in the absence of any FcR cross linking. Activated human T cells were used to evaluate antibody induced proliferation and cytokine release.

Effects of these antibodies on regulatory T cell Treg suppression of T effector proliferation and cytokine release were measured. Improved binding was due to the enhanced avidity of the multivalent IgMs compared to bivalent IgGs. In primary human T cell activation assays, IgMs significantly enhanced T cell proliferation and cytokine secretion compared to IgGs.

In co- culture of Tregs with T effector cells, IgM antibodies significantly reversed the suppressive activity of Tregs on T cell proliferation and inflammatory cytokine secretion, whereas IgGs had little to no effect. Efficient multimerization and agonism of OX40 and GITR with IgM antibodies may therefore enhance the anti-tumor immunostimulatory effects of immunotherapeutic antibodies targeting these T cell agonists.

We thank Sarah Wadsworth for her assistance with some of the studies. This strategy delivers potent T cell costimulation, which is currently missing from checkpoint inhibitor only regimens, and may be critical for the generation of clinical anti- tumor responses, seeking to broadly improve cancer outcomes. ALPN has previously demonstrated preclinical anti-tumor activity superior to PD-L1 inhibition, but the specific mechanism s of superiority remain unreported.

Multiple doses of ALPN elicited anti-tumor responses superior to durvalumab as judged by tumor volume measurements. Efficacy was importantly also observed with single ALPN doses administered intraperitoneally or intratumorally. Ongoing studies seek to further define such potential and specific clinical indications and modalities to guide upcoming clinical trials. Agonistic antibodies against CD have shown promising therapeutic activity in mouse tumor models. However, hepatic toxicity has been observed in animals and humans with a few anti-CD antibodies [1,2].

Recent advances in our understanding of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as important contributors to function [3,4]. Here we describe the preclinical characterization of CTX, a fully human IgG4 agonist of CD with a differentiated pharmacology and toxicology profile. CTX was identified based on epitope binning and antigen-binding assays.

The in vivo efficacy of CTX was assessed in multiple syngeneic mouse tumor models that included various mechanistic endpoints: FACS analysis of TILs, effector cell depletion, tumor histology, and Fc receptor profiling.

Finally, the toxicity profile of CTX was evaluated in mice and cynomolgus monkeys. CTX binds to a unique epitope shared by human, cynomolgus monkey, and mouse CD All mice cured by CTX rejected tumors upon rechallenge. CTX profoundly reprogramed the TME, leading to an influx of inflammatory cells, decreased T cell exhaustion, Treg depletion, and TAM modulation, while having very little effect on the peripheral immune system.

IND-enabling toxicology studies are underway, and a Phase 1 trial is planned for the first-half of Activation of BB on liver myeloid cells triggers hepatitis via an interleukin—dependent pathway. Clinical Cancer Research. Results from an integrated safety analysis of urelumab, an agonist Anti- CD monoclonal antibody. Complex interplay between epitope specificity and isotype dictates the biological activity of anti-human CD40 antibodies. Cancer Cell.

A series of fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency. Cell Death Differ. In animal models, agonistic antibodies targeting the T cell costimulatory receptor BB CD have shown promise as anti-tumor agents, but clinical studies have shown only limited signs of efficacy as well as dose-limiting hepatotoxicity with one of the candidates.

To avoid systemic toxicities and to direct immune activation to the tumor, we have generated the tumor-targeted BB agonist MP Previously we have shown, in vitro and in vivo, that MP is at least as potent as the agonistic BB antibodies and, in contrast to the antibodies, does not induce hepatotoxicity or exacerbate graft versus host disease in humanized mouse models.

Also, no systemic T cell activation has been observed in cynomolgus monkeys. Mice were then treated with a suboptimal dose of a tumor associated antigen binding T cell engager and with a variant of MP containing a mouse FAP binding domain mMP at doses from 0.

Tumor volume and potential biomarkers of T cell activation were measured. Only marginal activity on T cells was seen at a dose of 0. In addition, mMP enhanced tumor regression induced by the T cell engager in a manner suggesting dose-dependency starting at 0. Dose dependency of pharmacodynamic activities related to BB RO has been demonstrated and biomarkers for clinical development have been identified.

Peripheral blood from all patients was monitored for type-2 IFN cytokine levels, gene expression, and lymphocyte phenotype by flow cytometry up to day As of 1 March , 40 patients have been dosed in the DE 28 and pharmacodynamic 12 cohorts. MEDI pharmacokinetics was dose-proportional over a range of 1.

Antidrug antibodies were rare and had minimal impact on pharmacokinetics. STING activation leads to interferon production and activation of inflammatory pathways that facilitate cytolytic T cell priming. STING agonists administered intratumorally show potent anti-tumor efficacy in a range of preclinical models; several agonists are in clinical development.

We hypothesize that by conditionally enhancing STING activation, ENPP1 inhibitors will facilitate development of anti-tumor cellular immune responses, particularly following radiation therapy. Mice were followed for outcome, tumor antigen specific T cell responses and changes in the tumor immune environment. Additional studies were conducted in mice bearing MC38 tumors. Therapeutic doses of MV were well tolerated in mice, with no evidence of toxicity or clinically-significant increases in systemic cytokine levels.

Systemic administration of MV- monotherapy caused tumor growth delay. MV combined with radiation therapy significantly increased overall survival, and most animals achieved durable tumor cures. Additional studies in the MC38 model confirmed MV activity.

Studies characterizing effects of MV in the tumor microenvironment are underway. We demonstrate for the first time that, in combination with radiation therapy, ENPP1 inhibition improves outcomes and cures tumors in preclinical models through changes in the tumor immune environment. These translational studies represent a novel approach to enhancing tumor directed immune response following radiation, and provide a foundation for clinical development of an ENPP1 inhibitor as a cancer immunotherapy.

Their therapeutic potential has been well established in animal models and human trials. As potential drugs, both IL2 and IL15 are extremely potent and suffer from low tolerability and very fast clearance that limits therapeutic window. Tolerability, immune stimulation, and pharmacokinetics were evaluated in non-human primates NHP. In both in vivo settings, a marked inverse correlation of pharmacodynamics and clearance was observed, with reduced potency variants allowing higher, more tolerated doses and enhanced lymphocyte proliferation due to more sustained exposure.

A lead candidate XmAb was selected based on combined experimental observations and modeling predictions, and has been selected for clinical development. We identified a variant, named XmAb, that optimally balanced potency and exposure. Our laboratory has previously shown that immunogenic tumors spontaneously activate the innate immune system through the STING pathway.

Based on this notion, STING agonists have been pursued as a pharmacologic approach to activate the pathway. Further biochemical techniques including Western blotting and intracellular immunofluorescence were used to carefully analyze each step of the STING pathway in tumor cells or controls. Uncovering the detailed molecular mechanism of this effect could lead to new therapeutic interventions to restore the STING pathway in cancer cells. In the same model FAP-IL2v further enhances the efficacy of PD-L1 checkpoint inhibition when combined with an agonistic CD40 antibody resulting in long term survival in the majority of animals, and in the induction of immunological memory as evidenced by protection from tumor cell re-challenge.

The presented efficacy studies support the role of the FAP-targeted immunocytokine FAP-IL2v as a versatile combination partner for cancer immunotherapy and serve to inform the selection of combination partners for clinical studies. Based on these data FAP-IL2v is currently being tested in Phase 1b clinical trials in combination with atezolizumab, trastuzumab and cetuximab.

However, a substantial number of patients fail to respond or become resistant to these therapies. Thus, combination therapies which include these agents as well as therapies targeting alternative effector cell types are needed. IL promotes survival and cytotoxicity of both CD8 T and NK cells in the absence of the concomitant expansion of Treg population, making it a strong candidate for immunotherapy. Direct administration of IL proved to be clinically challenging; durability of responses likely hindered by the short half-life and toxicity.

Initial assessment of this fusion antibody showed enhanced tolerability relative to a non-targeted IL fusion antibody and potent anti-tumor activity. Mouse syngeneic tumors were grown to mm3 prior to a single IV administration of KDsurrogate. Immune cell activation in cynomolgus monkeys was assessed following IV administration of KD Day 1 and Where applicable, tumor volumes were measured and immune cell infiltration and modulation was evaluated by immunohistochemistry, flow cytometry and Luminex.

To assess broad anti-tumor potential of our molecule, single dose of KDsurrogate was tested against a panel of 12 murine syngeneic tumors. Pronounced tumor growth inhibition was observed in multiple tumor types. In CT, colorectal tumor model, KDsurrogate treatment achieved complete tumor regression in multiple animals, and consistent with generation of immune memory, tumors in these animals failed to regrow following CT re- challenge.

Interestingly, KDsurrogate demonstrated synergistic response when co-administered with anti-PD-1 antibody, suggesting that KD could be effectively combined with other checkpoint modulators. Additionally, an increase in tumor CD8 cells was observed in mice treated with KDsurrogate compared to the non-targeted IL fusion antibody. KD treatment led to a robust activation of multiple effector cell types associated with a potent and durable anti-tumor activity.

Based on the therapeutic activity and improved safety of the fusion protein, Kadmon is developing KD with the aim of clinical testing in Interleukin-2 IL-2 is a cytokine immunotherapy approved by the FDA in that shows rare, but dramatic activity in metastatic renal cell carcinoma and melanoma. However, IL-2 therapy is hampered by limited efficacy, severe toxicities, and a short circulating half-life that necessitates frequent administration.

These limitations may be overcome by engineering IL-2 variants with extended half-life and decreased reliance on the IL-2 accessory receptor CD25 that is believed to mediate toxicity and unwanted stimulation of Tregs. These Superkines were assayed for in vitro signaling potency on IL-2 receptor reporter cells lines and human peripheral blood mononuclear cells PBMCs. Selected muteins were evaluated for their efficacy in syngeneic mouse models and for their in vivo PK and safety.

This change improved IL-2 receptor dimerization in human cell lines and greatly enhanced phospho-STAT5 signaling and proliferation of CD8 lymphocytes vs. MDNAFc was characterized at multiple doses and with several administration methods, demonstrating a greatly extended serum half-life that enabled a semiweekly to weekly subcutaneous dosing schedule in mice, paired with a good safety profile in vivo.

MDNAFc is an improved interleukin-2 agent with a unique biased activation profile targeting effector versus immunosuppressive immune cells, and improved efficacy in a melanoma model. MDNAFc could improve the therapeutic potential of an effective, but limited use IL-2 immunotherapy by improving its efficacy, safety, and dosing convenience, a profile that may synergize well with immune checkpoint therapy.

Successful development of cytokines as immunotherapeutics for the treatment of cancer requires defining the optimal treatment regimen[1]. Post-infusional reactions limited dose escalation and immune activation in the first- in-human clinical trial of recombinant human IL rhIL given as a minute intravenous bolus IVB [2]. The most common adverse events were fever, chills, fatigue, nausea, transient liver function test abnormalities, anemia, and thrombocytopenia Tables The best response was stable disease.

Impressive expansion of NK cells was seen at all dose levels 21 to fold, mean fold as well as an increase in CD8 cells 1. This effector lymphocyte expansion exceeded results seen with other rhIL- 15 dosing regimens or other IL formulations Table 4. The shorter duration of the CIV-5 rhIL regimen and its safety profile may make outpatient administration via an ambulatory infusion pump feasible. Conlon, K. Miljkovic, and T. Waldmann, Cytokines in the Treatment of Cancer. J Interferon Cytokine Res, J Clin Oncol, Cancer Research, Miller, J.

Clinical Cancer Research, Miljkovic, M. Aldesleukin, a recombinant form of IL-2, is the first approved immuno-oncology drug leading to complete, durable remissions in metastatic melanoma and renal cell carcinoma patients. Yet, its use is very limited because of vascular leak syndrome VLS , a severe dose-limiting adverse event stemming from the engagement of the high affinity IL-2 receptor alpha chain in group 2 innate lymphoid cells, eosinophils and vascular endothelial cells.

In non-human primates, SYTXA can be dosed for maximal elevation in lymphocytes pharmacodynamic marker with negligible elevation in eosinophils toxicology marker. IL is a cytokine that activates and provides survival benefit to T and NK cells and has potential as an immunotherapeutic agent for the treatment of cancer. Exploiting the therapeutic value of native IL has been challenging due to, for example, its unfavorable pharmacokinetic properties and tolerability.

NKTR is a polymer-conjugated human IL that retains binding affinity to the alpha subunit of IL receptor and exhibits reduced clearance to thereby provide a sustained pharmacodynamics response. For in vivo NK cell characterization, mice received single IV doses of 0. Blood and spleen samples were collected to assess the NK population and function. In the CT26 model, 1x cells were administered intravenously on Day 0, treatment was initiated on Day 1 at 0.

In the orthotopic 4T1 model, 5x cells were implanted in the mammary fat pad on Day 0, treatment was initiated on Day 5 at 0. In the disseminated CT26 model, NKTR treatment resulted in a significant increase of NK cells in lung and a dose-dependent reduction in the number of lung metastases in a NK cell-dependent manner.

In the physiological 4T1 metastasis model, NKTR- also showed a significant anti-metastatic effect although it did not affect primary tumor growth. NKTR is a powerful immune stimulator of NK cells that provides a dose-dependent effect in the proliferation and activation of NK cells. This property of NKTR translates into enhanced anti-metastatic activity in mouse lung metastasis models.

These results indicate that NKTR has the therapeutic capacity to be an anti-tumor agent that enhances NK cell expansion and survival. NKTR has shown promising clinical results by enhancing systemic anti-tumor responses. Radiation therapy RT alone rarely generates an effective in situ vaccination due, in part, to poor persistence of activated tumor-specific lymphocytes.

However, RT can increase tumor immunogenicity by local release of immune stimulatory cytokines, immunogenic tumor cell death, and phenotypic changes that enhance immune susceptibility of tumor cells surviving RT. NKTR may sustain, expand, and drive the systemic anti-tumor response initiated by RT leading to tumor clearance and tumor specific immunologic memory. Cohorts of mice were then treated with one of the following: 1 intravenous IV IL-2 0. Tumor growth was monitored biweekly. All mice with complete response CR were rechallenged at day 90 with a second inoculation of B78 melanoma to test for immunologic memory.

Daily single intravenous Interleukin-2 IL-2 infusions pulses have been developed to decrease toxicity while maintaining anticancer activity of this molecule against melanoma. Hank has demonstrated in vitro that LAK generated by IL-2 then subsequently exposed to additional IL-2 displayed enhanced cytotoxicity [2]. In patients receiving IL-2 therapy, a rebound lymphocytosis occurs approximately days later.

The staccato schedule was developed to administer an additional IL-2 pulse during the time of rebound lymphocytosis. Cycles were repeated every 3 weeks. Prior systemic therapy: Ipilimumab 8 ; Interferon 7 ; Pembrolizumab or Nivolumab 7 ; Interleukin-2 5 ; oral targeted therapy 4 ; none 4. No patients required hospitalization for toxicity of therapy. Two of the patients with partial responses have been rendered free of disease following surgical resection of their residual cancer.

Responses occurred in lung, bones, lymph nodes, pancreas, peritoneum, breast, small bowel, and subcutaneous sites. Median response duration is Low-dose cyclophosphamide and low-dose interleukin-2 for malignant melanoma. Bull NY Acad Med ; Addition of interleukin-2 in vitro augments detection of lymphokine-activated killer activity generated in vivo.

Cancer Immunol Immunother ; Pegilodecakin is a PEGylated-recombinant hIL that has single agent and combination efficacy with chemotherapy and checkpoint inhibitors across multiple cancers. Microtubule inhibiting molecules are used as chemotherapeutic agents but combination efficacy with immuno-oncology therapies is not well understood.

Here we report the enhanced immune responses and efficacy of AM when combined with Docetaxel. Pegilodecakin is active, but immunogenic in mice. Therefore, B-cell deficient mice were employed for in-vivo studies. Mice received Pegilodecakin alone at 0. Tumor size and body weights were monitored twice weekly.

Immune cells were phenotyped by flow cytometry. Sera were analyzed for cytokines. The control cohort reached the terminal tumor size by Day 39 PI. Systemic metastases were only observed in control and Docetaxel cohorts. IFNG was undetectable in control mice at 3 weeks and not available at the terminal endpoint. The immune stimulation of the combination therapy is further reflected in the systemic increase of IFNG in the combination arm compared to monotherapy.

These results provide rationale to clinically test a combination Docetaxel with Pegilocakin in tumors with low T-cell infiltration and resistance to available immunotherapies. IL has anti-tumor activity but with limited efficacy due to its unfavorable pharmacokinetic properties and tolerability. Nektar Therapeutics has developed a polymer-conjugated human IL NKTR that exhibits a prolonged in vivo half-life and enhanced potency, which is currently being examined as a potential cancer immunotherapeutic agent.

ALKS has previously been shown to have enhanced antitumor activity relative to IL-2 in murine models. In the ongoing FIH Phase 1 study in patients with advanced solid tumors, ALKS is administered as a 30 minute intravenous infusion once daily for 5 consecutive days repeating in treatment cycles of 14 days first cycle or 21 days subsequent cycles.

The primary objectives are to investigate ALKS safety and tolerability and to determine the maximum tolerated dose and recommended Phase 2 dose. Other assessments include pharmacokinetics, lymphocyte sub-population expansion, immunogenicity, and anti-tumor activity. Twenty-four patients have received ALKS at doses ranging from 0. Patients with multiple tumor types were enrolled, including 5 with prostate carcinoma, 4 with renal cell carcinoma, and 3 with melanoma.

Patients had a median of 3 range prior lines of systemic therapy. There were no Grade 4 or 5 AEs. Transient, dose dependent elevations in serum IL-6 levels occurred hours post-dose and were associated with transient fever and chills but not cytokine storm. No objective responses have been seen, and dose escalation is ongoing.

ALKS was well tolerated at the doses tested, with treatment-related AEs that were manageable and transient. Study was sponsored by Alkermes, Inc. The authors gratefully acknowledge the patients and their families who participated in this study. Trial Registration at Clinicaltrials. High dose IL-2 has been used in treatment of metastatic melanoma and renal cell carcinoma. However, expansion of suppressive Tregs and physiologic toxicities associated with IL-2 has limited its use in anti-cancer therapies.

Tumor size, survival and tumor-specific effector T cell response was analyzed. NKTR efficiently synergized with checkpoint blockade and with vaccination, improving overall survival and cure of mice in models of colon carcinoma and melanoma.

In vitro cytokine treatment also confirmed that IFN-gamma and TNF-alpha together are both sufficient and required to block Treg proliferation. Preliminary results confirm similar therapeutic effects with cancer patients receiving clinical doses of NKTR To compare the pharmacodynamic responses in response to the intravenous and subcutaneous administration of ALKS , two studies were carried out in cynomolgus monkeys.

In the first study, a single dose of ALKS was administered intravenously or subcutaneously. In the second study, ALKS was administered intravenously once daily on Days or subcutaneously on Days 1 and 4. Serial blood samples were collected from each animal for determination of serum concentrations of ALKS and multiple proinflammatory cytokines as well as for immunophenotyping by flow cytometry.

Overall systemic exposure to ALKS as measured by area under the serum concentration vs. Total systemic exposure to ALKS was comparable after 5 daily intravenous doses of 0. Therefore subcutaneous administration may be a practical alternative to intravenous dosing and merits clinical evaluation. Immune-checkpoint blockade treatments, particularly drugs inhibiting programmed death-ligand 1 PD-L1 with its receptor, programmed cell death protein-1 PD-1 has demonstrated promising clinical efficacy in patients with advanced non-small cell lung cancer NSCLC.

The complex nature of the host immune response makes tissue based biomarker development for IO response assessment challenging. Consequently, there is an urgent and critical unmet need to develop accurate, validated biomarkers to predict which NSCLC patients will benefit from IO.

Previous research has shown that the morphology of the tumor feeding vessels plays a role in cancer aggressiveness as well as therapeutic refractoriness. Post-treatment tumors show significant improvement in vessel tortuosity abnormalities when compared before therapy initiation. Hence, we sought to evaluate whether computer extracted measurements of fractal features of nodule associated vessel morphology on baseline CT scans in NSCLC patients treated with Nivolumab could distinguish between patients who did and did not respond to the PD-1 inhibitor.

Our study comprised non-contrast CT scans of 61 patients obtained retrospectively from the Cleveland Clinic, including 31 patients who responded to Nivolumab and 30 non-responders. From nodule annotations provided by a trained radiologist, a region-growing algorithm was used to segment the surrounding vasculature Figure1A. A set of 12 vessel fractal radiomic VFR measurements pertaining to the fractal analysis, the state space reconstruction and Lyapunov exponent were extracted from each nodule associated vasculature.

A Naive Bayes classifier was then used, in a 3-fold cross-validation setting through iterations, to construct a classifier to identify which patients respond to nivolumab therapy. The VFR could potentially serve as a predictive tool for response assessment for immune checkpoint inhibitors and enable selection of NSCLC patients who will benefit from IO; paving the way for design of more rational clinical trials with combination of IO agents.

Despite the success of immunotherapy in several cancers, antibody blockade of the immune checkpoint receptor PD-1 failed to improve the survival of recurrent glioblastoma multiforme GBM patients [1]. In contrast to this clinical reality, the widely used immunocompetent mouse model of GBM, GL, is highly immunogenic and readily cured by T-cell checkpoint blockade therapy [2]. The resulting inability to model the immunotherapeutic sensitivity of human GBM preclinically prevents effective translation of murine observations to clinical therapies.

Quaking QKI is a GBM tumor suppressor gene which is deleted, mutated or downregulated in the majority of human GBM [3,4], the expression level of which strongly correlates with patient survival [5]. The immunotherapeutic sensitivities in response to systemic CTLA-4 and PD-1 blockade therapies were determined by tumor growth kinetics and survival.

The tumor microenvironment TME was evaluated by flow cytometry analysis. These QPPs have distinct sensitivities to systemic checkpoint blockade in different niches. The distinct checkpoint blockade sensitivities of QPP lines could fill the critical need for preclinical GBM models suitable for evaluating immunotherapeutics. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res. From the cover: neutralization of terminal differentiation in gliomagenesis.

The somatic genomic landscape of glioblastoma. Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation. Nat Genet. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy.

Neuro Oncol. PD-L1 expression and prognostic impact in glioblastoma. Spatial characterization of the tumor microenvironment TME interface between cancer cells, stroma and immune cells is essential for understanding tumor progression and discovering prognostic and predictive biomarkers. However, it has proven difficult to perform such studies in a highly multiplexed manner using limited sample quantity.

Digital Spatial Profiling DSP has been developed as a research use instrument, software and chemistry for hi-plex profiling of mRNA and protein using an optical-barcode read-out. In this study, microsatellite stable MSS or instable MSI characterized colorectal tumors were characterized using DSP with 40 proteins or 48 RNA probes to evaluate active and suppressive immune mechanisms in both immune dense regions and tumor versus stroma.

Sixteen FFPE colorectal tumors that were characterized for Microsatellite stability status were mounted on slides. Two strategies were used for selecting ROIs, 1 Geometric profiling of CDenriched hotspots in the tumor center and invasive margin and 2 Segment profiling of cytokeratin-positive tumor regions compared to cytokeratin-negative regions.

We show that deep profiling of CDenriched regions from the invasive margin and tumor center of MSS and MSI tumors have different immunosuppressive and activated immune phenotypes. Further evaluation using segment profiling of tumors versus stroma also identified specific immune proteins and RNA pathways that were distinctly related to each compartment and were different between MSI and MSS tumors.

Malignant mesothelioma is an aggressive cancer with poor prognosis and few effective therapies. Since mesothelioma is derived from the mesothelium of the lung, we hypothesize that immune cells in the tumor microenvironment TME may behave differently than other solid tumors. In our previous studies, utilizing multi- plexed immunofluorescence, we did not find immune phenotypes associated with improved patient survival.

Here we describe a novel combination of two technologies to spatially characterize the interface between mesothelioma cells, stroma and immune cells in the TME in a high-plex capacity. Definiens analysis was combined to identify localization of each marker in the tumor center, invasive margin or stroma. We found strong correlation between Definiens and NanoString analysis of T cell and macrophage markers in selected regions.

Co-localization analysis revealed that high CD68 density was tightly correlated to PD-L1 expression and in at least one case additional suppressive macrophage markers, including CD and B7-H3. Already this small data set demonstrates that integration of two novel high-plex spatial analysis techniques separates distinct immune mechanisms in the TME.

Our analysis suggests that macrophages are highly associated with expression of immune-inhibitory signals in mesothelioma. Therefore, we hypothesize that analysis of additional mesotheliomas may guide the development of combination immunotherapy trials that will be effective against this incurable disease.

Pseudoprogression PsP is an inflammatory response associated with radiation and necrotic induced changes reflective of treatment, appearing as areas of increased enhancement on postcontrast T1-weighted images. Advanced imaging techniques MR perfusion, MR diffusion have been proposed as an alternative way of distinguishing between PsP and progressive disease PD.

However, the outcome of such studies underscores the need for novel tools distinguish between these. Patients: A total of 98 patients were included in this multi-institutional IRB-approved study. All had pathological confirmation; 78 patients with PD and 20 patients with PsP. Images were analyzed using Nordic ICE 2. The extracted 3D region-of- interest ROI parametric maps were imported in the radiomic pipeline. A total of features 10 histogram-based and higher-order texture features were calculated for each parametric map.

Finally, box plots of the 10 most relevant features and probability maps were calculated. Area under the curve AUC , sensitivity and specificity were Box plots of the 10 most relevant features are shown in Figure 3. Further validation and a comparative study of radiomic analysis of MR perfusion maps and conventional MR images would be valuable to determine which approach is more effective, and the added value in combining the two approaches.

Treatment-related changes can occur as a result of multiple factors; these changes are often difficult to distinguish from true progression PD of the tumor using conventional MRI. Treatment-related changes or pseudoprogression PsP subsequently subside or stabilize without any further treatment, whereas progressive tumor requires a more aggressive approach.

Hence, it can predispose a patient to overtreatment or be categorized as a non-responder and exclude him from clinical trials. Radiomic analysis results in the quantification of grey tone spatial variation thereby providing textural features that characterize the underlying structure of the object under investigation. In this multi-institutional study, we evaluated GBM patients retrospectively.

Conventional MR images were acquired using typical clinical acquisition parameters. A total of radiomic features were obtained for each patient. Five texture features i. The proposed tool has the potential to advance clinical management strategies. Increase in tumor mutation burden TMB or hypermutation is the excessive accumulation of DNA mutations in cancer cells. Hypermutation was reported in recurrent as well as primary gliomas.

Hypermutated gliomas are mostly resistant to alkylating therapies and exhibit a more immunologically reactive microenvironment which makes them a good candidate for immune checkpoint inhibitors. Radiomic analysis was performed on the conventional MR images FLAIR and T1 post-contrast obtained prior to tumor tissue surgical sampling; and rotation-invariant radiomic features were extracted using: i the first-order histogram and ii grey level co-occurrence matrix.

ROC analysis and a split for training and testing, were used to assess the performance of logistic regression classifier and AUC, Sensitivity, Specificity, and p-value were obtained. Figure 1. Figure 2, 3, 4. We describe two advances in multispectral fluorescence immunohistochemistry, a powerful tool for quantifying interactions within the tumor microenvironment. First, a fully-automated 8-plex assay plus DAPI counterstain on the same tissue section.

Colors assigned to each marker, and associated component planes, are shown in Figure 1B. To interrogate interactions across a whole section, we additionally developed a multispectral whole-slide scanning method, demonstrated on lung cancer using a subset of 7 stains from the 9-color panel above.

Phenotype and expression-level assessments of the unmixed whole slide scan describe distribution patterns of immune cells across the entire section. We introduce a 9-color fIHC assay that distinguishes 8 markers plus DAPI counterstain on the same tissue section, increasing the depth of cellular interactions that can be studied within the tumor microenvironment.

Additionally, we introduce a whole slide multispectral imaging method that provides rich quantitation of interactions among 6 markers at length scales spanning from cell biology to tumor physiology. Chimeric antigen receptor CAR T cell therapy has demonstrated success in clinical trials [1], and two such therapies have now been approved within the USA [2].

Due to the heterogeneity of apheresis products from heavily treated cancer patients, no algorithms exist to predict the efficacy of manufactured CAR T cell products. CAR T cells are living drugs, that are capable of division, anti-tumor cytotoxicity and cytokine secretion post infusion. Based on previous models of virus-T cell interaction [3], we developed new models to estimate post-infusion CAR T cell division and cytotoxicity. Fitting of model parameters to published patient data and model inference performed using ABC-SysBio [6], a python-based toolkit implementing Approximate Bayesian Computation.

Any of the models developed selection shown in Figure 1 could be fit to patient data, and ABC-SysBio can be implemented to select between the models given patient data. Broadly, the rates of division of high performance clonal CAR T cells at most 4 h doubling time , and the rates of memory formation of CAR T cells at least 0.

Surprisingly memory formation is more associated with complete remission than cytotoxicity and mirrors previous findings that correlate therapeutic success with memory formation [7]. Estimation of the parameter values for number of CAR T cell divisions, rates of division, memory formation, memory reactivation, CAR T cell depletion exhaustion and non-exhaustion induced death and anti-tumor cytotoxicity can be useful in determining the design specifications of successful CAR T cell therapy administrations across various clinical trials.

Extrapolation of this model in a prospective setting will be needed for further validation. Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev. June, CH, Sadelain M. Chimeric Antigen Receptor Therapy. N Engl J Med. Wodarz D,Thomsen AR.

Effect of the CTL proliferation program on virus dynamics. International Immunology. Hoops S, et al. Burda, BU, et al. Estimating data from figures with a Web-based program: Considerations for a systematic review. Res Synth Methods. Liepe J, et al. Fraietta JA, et al. Determinants of response and resistance to CD19 chimeric antigen receptor CAR T cell therapy of chronic lymphocytic leukemia.

Nat Med. The myeloid cell compartment plays an important role in anti-tumor immune responses and represents a heterogeneous population with both cancer-promoting and cancer-restraining actions. Unleashing the full potential of cancer immunotherapies requires an understanding of the cellular mechanisms that govern these opposite actions. To date, high throughput relevant preclinical models for dissecting the interactions between different cellular players in the tumor microenvironment are lacking.

Previously we have shown that our 3D image-based co-culture system allows assessing efficacy of immune modulators to enhance PBMC infiltration and tumoroid killing. Our main goal was to improve this model by incorporating a more complete human immune system. To do that we first generated diverse myeloid populations in a 3D environment and then used our image-based platform to describe the different subsets. The image analysis software was trained on a set of features that reproducibly allowed discrimination between undifferentiated monocytes, M1 and M2 macrophages and dendritic cells.

The different myeloid subsets were next co-cultured with tumor cells to analyze the complex cellular interplay of the TME. The cellular interactions were visualized using high-content microscopy and quantified with multiparametric morphometric analysis with OMinerTM software. Our approach also enables the analysis of how tumor-driven mechanisms regulate myeloid cell differentiation and contribute to the immunosuppressive microenvironment.

These results provide a means to elucidate the bi-directional interplay between tumor and immune cells and allows for analysis of functional reprograming of the suppressive population towards a M1 phenotype induced by drug candidates.

The 3D assay presented here enables visualization and measurement of effects of immunotherapies on cells that engage in a more physiologically relevant spatial setting than when culturing them in traditional 2D cultures. Using morphological measurements different myeloid cell subsets can be distinguished, which offers a very attractive alternative for complex and labor-intensive phenotyping based on markers expression and cytokine release profiling.

The ultimate goal is to develop a highly sophisticated platform for testing cancer immunotherapies that combines the complexity of the TME and the robustness of a high throughput screening platform. Core needle biopsies are used to histologically assess tumors when surgical excision is impractical.

Initially, 20 immunolabeled slides from purchased non-squamous NSCLC tumor resections were scanned and tumor region was manually annotated[1]. Needle biopsies were simulated using an elliptical shape, with multiple iterations applied by varying the size, angle and positioning of that ellipse across the full resection using Python programming language[3], totaling in 24, single needle simulations per case. Using the statistical software R[4], individual cores were compared to other cores in each sample, to the full tumor region and across all 20 cases.

Determining a clinically-feasible number of cores to accurately assess CD8 requires further study. Systematic measurement of sampling error should be extended to other markers of the immune response to cancer whose expression is known to be heterogenous, such as PD-L1. J Immunother Cancer ; R Core Team R: A language and environment for statistical computing. It has been a challenge to apply immunotherapy IT to patients with chordomas, due to lack of clinically-translatable in vivo models.

Currently, there are no well-established murine chordoma cell lines that can be injected to syngeneic mice or no transgenic mouse models that develop chordomas spontaneously, which would allow us to study the interaction between murine chordomas and murine immune cells. Hence, we aimed to develop a humanized mouse model, where human immune cells are engrafted into immunodeficient mice,[1,2] to overcome this limitation by studying the interaction between human immune system and human chordomas.

We also sought to utilize it to study synergistic effect between IT and radiation therapy RT against chordoma. Fifteen week-old NSG mice were sub-lethally 1. During and after the treatment, anti-tumor activities were monitored via tumor size, flow cytometry, qRT-PCR, and immunohistochemistry. We demonstrated that this humanized mouse model could be a revolutionary platform to investigate IT against rare cancers such as chordomas, where murine equivalent cell lines are currently unavailable.

The direct synergistic effect between IT and RT against chordoma as well as the potential abscopal effect was observed. Alan Meeker and Sujayita Roy. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A model for personalized in vivo analysis of human immune responsiveness.

Sci Transl Med. Mouse models in oncoimmunology. Nat Rev Cancer. The tumor associated glycoprotein MUC16 is highly expressed in ovarian cancer with limited normal tissue expression, making it a suitable target for the development of CD3 binding T-cell engaging bispecific antibodies. Here we used non-invasive immuno-PET imaging as a powerful tool to determine the impact of each antigen binding arm on bio-distribution of MUCCD3 bispecific antibodies in mice.

Antibodies were radiolabeled with positron emitting radionuclide Zirconium 89 Zr using the chelator deferoxamine DFO and demonstrated high radiochemical purity and immunoreactivity. Tumor uptake between the antibodies was generally not significantly different despite the high lymphoid uptake of 89 Zr- MUCCD3 high.

This work demonstrates that immuno-PET is an ideal technology to monitor bispecific localization in vivo. Further studies may investigate any correlation between antibody biodistribution as monitored by immuno-PET and toxicity or efficacy observed during the optimization of these promising therapeutics.

Immuno-oncology has revolutionized cancer care for many cancer types, however, the development of novel immunotherapeutics still faces many challenges due to lack of drug screening platforms that represent the complexity of the tumor microenvironment. Conventional cytotoxicity assays, such as chromium 51 and LDH release are limited in providing clinically relevant data about immunogenic cell death. The goal of this study was to develop an integrated confocal-based high-throughput, high-content real-time imaging platform to assess immunogenic cell killing activity of novel immunotherapeutic agents and to develop rational drug combinations using patient-derived tumor samples.

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