Immune Checkpoint Modulators Research Articles

Cancer patients' experiences with immune checkpoint modulators: A qualitative study.

BackgroundMinimal qualitative data exist on the experiences of cancer patients treated with immune checkpoint inhibitors or costimulatory antibodies. Understanding the day to day experiences of patients being treated with immune checkpoint modulators, and how these relate to their health‐related quality of life, can inform future research and lead to better clinical decision‐making and care. We report here the first in depth qualitative study to consider patients' diverse and complex experiences with immune checkpoint modulators, with a focus on side effects and how these impact daily life.MethodsThis single‐center qualitative study was based on focus groups and semistructured interviews. Patients who were being treated or who had been treated with immune checkpoint modulators within the last year for a range of cancer diagnoses were recruited. Interpretive description informed our inductive, iterative approach to analysis.ResultsEight themes were identified, characterizing the complexity of these patients' lived experiences: major categories of side effects experienced and how they impacted patient well‐being; the heterogeneous nature of side effects experienced; living with uncertainty; reframing the meaning and severity of SEs; focus on survival, hope, and being positive; acceptance and adaptation; feeling supported; and faith in medical innovation. Throughout their accounts, participants highlighted the profound impact that immune checkpoint modulators had on their daily lives.ConclusionThis is the first in‐depth qualitative study into patient accounts of their experiences of treatment with immune checkpoint modulators, related side effects, and how it impacted their daily lives. This research is an integral initial step in developing an instrument that will assess treatment‐related side effects in patients treated with this form of therapy.

Immune checkpoint modulation enhances HIV-1 antibody induction

Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

Development of the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM): A toxicity subscale to measure quality of life in patients with cancer who are treated with ICMs.

Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL. Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale. Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items. To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients.

Development of a Functional Assessment of Chronic Illness Therapy item library and primary symptom list for the assessment of patient-reported adverse events associated with immune checkpoint modulators.

Aim:To develop a comprehensive item library of patient-reported, immunotherapy-related adverse events (irAEs) that draws from and expands on the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System.Methods:Literature review and iterative expert input. Based on a literature review of irAEs, we developed a framework of immunotherapy classes and their associated symptoms. Clinical experts then reviewed iterations of symptom summaries and item maps linked to the immunotherapy framework. Experts provided content review and feedback was shared across experts until consensus was reached. The iterative process facilitated creation of a Primary Symptom List associated with immune checkpoint modulators (ICMs), drawn from the larger set of symptoms. Existing FACIT items were mapped to the symptom list, and new items were written as needed to create the item library.Results:The full item library of irAEs is comprised of 239 items, covering 142 unique symptoms across 75 inflammatory reactions/immune conditions. A subset of 66 items comprises a Primary Symptom List considered most common/relevant to ICM treatment. This includes gastrointestinal, skin, pulmonary, neurologic, musculoskeletal, and multiple miscellaneous and constitutional symptoms.Conclusion:The FACIT Immunotherapy Item Library is a compilation of 239 self-report items that capture the wide range of AEs experienced by people receiving immune treatments. A subset of 66 items comprises a Primary Symptom List meant for ICM therapy. Use of items selected from this library is encouraged in clinical research and clinical practice evaluation.

Nanobodies as versatile tools: A focus on targeted tumor therapy, tumor imaging and diagnostics.

Monoclonal antibodies and vaccines have widely been studied for the immunotherapy of cancer, though their large size appears to limit their functionality in solid tumors, in large part due to unique properties of tumor microenvironment. Smaller formats of antibodies have been developed to throw such restrictions. These small format antibodies include antigen binding fragments, single-chain variable fragments, single variable domain of camelid antibody (so-called nanobody (Nb) or VHH). Since their serendipitous discovery, nanobodies have been studies at length in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from camelid heavy-chain antibodies, possess unusual hallmarks in terms of (small) size, stability, solubility and specificity, hence allowing cost-effective production and sometimes out performing monoclonal antibodies. In addition, these small camelid heavy-chain antibodies are highly adaptable tools for cancer research as they enable specific modulation of targets, enzymatic and non-enzymatic proteins alike. Molecular imaging studies benefit from the rapid, homogeneous tumor accumulation of nanobodies and their fast blood clearance, permitting previously unattainable fast tumor visualization. Moreover, they are endowed with considerable therapeutic potential as inhibitors of receptor-ligand pairs and deliverers of drugs or drug-loaded nanoparticles towards tumors. In this review, we shed light on the current status of nanobodies in diagnosis and imaging of tumor and exploiting nanobodies revert immunosuppressive events, modulation of immune checkpoints, and as deliverers of drugs for targeted tumor therapy.

Comprehensive Analysis of the Tumor Microenvironment in Cutaneous Melanoma associated with Immune Infiltration.

Accumulating evidence suggests that the malignant phenotypes of cancers are determined not only by the intrinsic properties of cancer cells but also by components in the tumor microenvironment (TME). In this study, we comprehensively characterized the TME of cutaneous melanoma (CM). As a result, tumor stage, tissue site, ulceration, thickness as well as patient age, sex were associated with immune infiltration. Patients of higher immune infiltration exhibited better survival outcomes, and antitumor effector cells, such as CD8 T cells and M1 macrophages, were found in significantly higher numbers in those tissues. Differential expression of mRNAs and long non-coding RNAs (lncRNAs) was analyzed and utilized to construct an immune-related competing endogenous RNA network, in which a lncRNA-associated subnetwork that could positively regulate the expression of IFN-γ was highlighted. Functional analysis confirmed that this network was remarkably enriched in functional terms related to both immune response and tumor-intrinsic pathways. Finally, a total of 109 high-confidence prognostic genes were identified, and a gene module that contained several key immune checkpoint molecules or modulators (PD-1, PD-L1, PD-L2, and LCK) was screened, which confers survival benefit for CM patients as supported by both overall and relapse-free survival rates from different datasets.

Combining Doxorubicin-Loaded PEGylated Poly(Lactide-co-glycolide) Nanoparticles with Checkpoint Inhibition Safely Enhances Therapeutic Efficacy in a Melanoma Model.

Doxorubicin (DOX) has been widely used for the treatment of various cancers, however, the use of soluble DOX is limited by its low therapeutic index and improved formulations are therefore sought. Aside from its tumoricidal properties, DOX has also been shown to cause an immunogenic form of cell death, however, it is becoming abundantly clear that in situ immune stimulation alone is insufficient to cause significant immune based antitumor activity and that immune checkpoint modulation is also required. In this study, DOX-loaded nanoparticles were made by nanoprecipitation of DOX with a PEGylated poly(lactide-co-glycolide) copolymer (DOX-PLGA-PEG NPs) and were then tested in combination with immune checkpoint blockade (antiprogrammed death (anti-PD-1)) in a murine melanoma model to enhance antitumor effectiveness. Results showed the prepared particles to be approximately 134 nm in diameter (zeta potential -22 mV) with a loading of 1.75 μg DOX/mg NPs. In vitro release studies (of DOX) revealed the NPs to exhibit a 12 h burst release phase, followed by a slower release phase for up to 200 h. Survival studies of mice challenged with B16.F10 melanoma cells, revealed 60% of mice treated with the combination of DOX-PLGA-PEG NPs plus anti-PD-1 were tumor-free at the completion of the study. This combination therapy demonstrated higher antitumor efficacy in vivo compared to control, soluble DOX, and monotherapy of DOX-PLGA-PEG NPs or anti-PD-1 solution (p < 0.05). Moreover, in vivo safety studies (mouse weight/histopathological/toxicity) were investigated and results suggested that the combination therapy was safe. In conclusion, this study demonstrates the successful fabrication of DOX-loaded NPs by a nanoprecipitation method, and when combined with checkpoint inhibition could provide significant therapy in a murine melanoma model, suggesting that the DOX-PLGA-PEG NPs may be generating immune stimulation in situ and that benefit from this combination may be obtained in a clinical setting in the future.

High CD3 and ICOS and low TIM-3 expression predict favourable survival in resected oesophageal squamous cell carcinoma

With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated. The value of immune markers, including programmed cell death ligand-1, programmed cell death-1 (PD-1), inducible co-stimulator (ICOS), lymphocyte activation gene-3, T-cell immunoglobulin, and mucin-dominant containing-3 (TIM-3), is not well known. Using tissue microarrays of 396 patients who underwent surgery for oesophageal squamous cell carcinoma (ESCC), infiltrated T-cell subsets (CD3, CD8, and Foxp3) and checkpoint protein expression were scored. With a median follow-up of 24.8 months, CD3+ TIL subsets (50.0%) had longer median recurrence-free survival (RFS, 55.0 vs 21.4 months) and overall survival (OS, 77.7 vs 35.8 months). Patients with high ICOS expression (46.5%) had longer median RFS (53.9 vs 25.3 months) and OS (88.8 vs 36.9 months). For PD-1, RFS (hazard ratio [HR] 0.67) and OS (HR 0.66) were significantly longer in the high-expression group (45.2%). In the multivariate analysis, high TIM-3 expression (50.8%) had a significant relationship with shorter RFS (HR = 1.52) and OS (HR = 1.60). High CD3+ TIL and T-cell ICOS expression were associated with favourable prognosis, whereas high TIM-3 expression suggested a poor prognosis. Our findings may confer new insights to improve ESCC outcomes beyond the application of PD-1 blockade.

STING Activation and its Application in Immuno-Oncology.

Recent regulatory approval of several immune checkpoint inhibitors has ushered in a new era of cancer immunotherapies with the promise of achieving a durable response. This represents a paradigm shift in cancer treatment from directly targeting tumor cells to harnessing the power of a patient's own immune system to destroy them. The cGAS-STING pathway is the major cytosolic dsDNA sensing pathway that plays a pivotal role in the innate antitumor immune response. With a fundamentally different mode of action (MOA) than immune checkpoint modulators, STING activation can potentially enhance tumor immunogenicity and improve patient responses as a single agent or by synergizing with existing anti-cancer drugs. Therefore, there has been intense interest from the pharmaceutical industry and academic institutions in the search for potent STING agonists as immunotherapies in oncology. In this article, we review briefly the cGAS-STING pathway and STING agonists that are in the clinical and preclinical studies, summarize recently disclosed patent applications and published journal articles in the field and cover both cyclic dinucleotide (CDN) analogs and non-nucleic acid derived STING agonists.

Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy.

The immune cells within the tumor microenvironment (TME) play important roles in tumorigenesis. It has been known that these tumor associated immune cells may possess tumor-antagonizing or tumor-promoting functions. Although the tumor-antagonizing immune cells within TME tend to target and kill the cancer cells in the early stage of tumorigenesis, the cancer cells seems to eventually escape from immune surveillance and even inhibit the cytotoxic function of tumor-antagonizing immune cells through a variety of mechanisms. The immune evasion capability, as a new hallmark of cancer, accidently provides opportunities for new strategies of cancer therapy, namely harnessing the immune cells to battle the cancer cells. Recently, the administrations of immune checkpoint modulators (represented by anti-CTLA4 and anti-PD antibodies) and adoptive immune cells (represented by CAR-T) have exhibited unexpected antitumor effect in multiple types of cancer, bringing a new era for cancer therapy. Here, we review the biological functions of immune cells within TME and their roles in cancer immunotherapy, and discuss the perspectives of the basic studies for improving the effectiveness of the clinical use.

Therapeutic Monoclonal Antibodies Targeting Immune Checkpoints for the Treatment of Solid Tumors.

Recently, modulation of immune checkpoints has risen to prominence as a means to treat a number of solid malignancies, given the durable response seen in many patients and improved side effect profile compared to conventional chemotherapeutic agents. Several classes of immune checkpoint modulators have been developed. Here, we review current monoclonal antibodies directed against immune checkpoints that are employed in practice today. We discuss the history, mechanism, indications, and clinical data for each class of therapies. Furthermore, we review the challenges to durable tumor responses that are seen in some patients and discuss possible interventions to circumvent these barriers.

Immunomodulatory aspects in the progression and treatment of oral malignancy.

Inflammation substantially affects the risk of oral malignancy. Pro-inflammatory cytokine, interferon (IFN)-γ, confers anti-tumor activity using several different mechanisms. Conversely, higher expression of interleukin (IL)-17 is associated with worse prognosis. Monocyte chemotactic protein (MCP)-1 correlates positively with poor long-term survival of head and neck squamous cell carcinoma (HNSCC) patients. IL-1α affects cancer associated fibroblasts and macrophages, and promote several malignant phenotypes including immune suppression. Some anti-inflammatory cytokines, including IL-10 and transforming growth factor (TGF)-β, relate to pro-tumoral activities.Among immune checkpoint modulators, programmed death (PD-)1 and PD-ligand (L)1 facilitate oral squamous cell carcinoma (OSCC) cell evasion from immune surveillance, and the expression status of these has a prognostic value.OSCCs contain tumor associated macrophages (TAMs) as major stromal cells of their tumor microenvironment. Among the two distinctive states, M2 macrophages support tumor invasion, metastasis and immune suppression. Crosstalk between TAMs and OSCC or cancer-associated fibroblasts (CAF) plays an important role in the progression of OSCC.Clinical trials with blocking antibodies against IL-1α or melanoma-associated antigens have been reported as therapeutic approaches against OSCCs. The most promising approach activating antitumor immunity is the blockade of PD-1/PD-L1 axis. Manipulating the polarization of pro-tumorigenic macrophages has been reported as a novel therapeutic approach.

1276P - Development of the functional assessment of cancer therapy-immune checkpoint modulator (FACT-ICM): A scale to measure quality of life in cancer patients treated with ICMs

BackgroundCurrently cancer patients treated with immune checkpoint modulators (ICMs) have their health related quality of life (HRQOL) measured by general patient reported outcome (PRO) tools such as the EORTC QLQC30 or Functional Assessment of Cancer Therapy-General (FACT-G). No instrument has been developed specifically for patients treated with ICMs, which may lead to their HRQOL being evaluated inaccurately. The objective of this study was to develop a toxicity subscale PRO instrument for ICM treated patients that would contribute to the measurement of HRQOL. MethodsInput was collected from a prior systematic review, patients and physicians. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed the development of an initial list of items that described ICM side effects (SEs) and their impacts upon HRQOL. Physician surveys and interviews informed subsequent item generation/reduction. Cognitive debriefing interviews were conducted with a new set of patients after they completed the toxicity subscale. ResultsFocus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. Following a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for ICM treated patients were surveyed with a list of 49 patient reported toxicity related unique SEs; and 11 physicians participated in follow up interviews. Informed by the data collected from the physicians, a second round of item reduction produced a list of 25 items that covered a wide range of SEs including but not limited to gastrointestinal, cutaneous, musculoskeletal, respiratory, constitutional, neurological and endocrine. This final list was piloted with 11 patients who confirmed that it was comprehensible and complete. ConclusionsThis 25 item list is the first HRQOL toxicity subscale developed with patient and clinician input for patients treated with ICMs. The subscale will be combined with the FACT-G to form the FACT-ICM and this PRO instrument will undergo further validity testing. Clinical trial identificationNCT02651831. Legal entity responsible for the studyPrincess Margaret Cancer Centre. FundingUniversity of Toronto, Strategic Innovation Grant. DisclosureA.R. Hansen: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution): Roche-Genentech; Advisory / Consultancy, Research grant / Funding (institution): MedImmune; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Boston Biomedical; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb. P. Bedard: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Servier; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly. All other authors have declared no conflicts of interest.

Exploring novel therapies in advanced soft tissue sarcoma: the path from multi-sarcoma to highly subtype-specific trials

Abstract Soft tissue sarcoma (STS) is a heterogeneous family of rare diseases comprising >70 subtypes, characterized by distinct morphological and genetic features. The orphan character and diversity of STS are barriers for the development of novel treatments. Drugs such as doxorubicin and ifosfamide, used in STS for >40 years, are considered standard of care until today, even though treatment outcome is poor. The approval of these agents was based on multi-sarcoma trials, but more recent trials of this kind failed to meet primary endpoints, such as Phase 3 studies with anthracycline (aldoxorubicin) and ifosfamide derivatives (pali-, evofosfamide), comparisons of single agent vs. combination therapy, or maintenance approaches (ridaforolimus). These trials did not reproduce efficacy signals observed in earlier trials, the most spectacular example being the failure of the Phase 3 trial with the PDGFRa-antibody olaratumab. The sarcoma field is now gradually moving towards a more histotype-specific exploration of new agents, which already led to regulatory approval of drugs such as trabectedin (lipo-, leiomyosarcoma) and eribulin (liposarcoma). Efficacy signals are easier to detect and more reproducible in subtype-specific clinical trials, and various classes of agents have already been tested using such approach. These include tyrosine kinase inhibitors such as crizotinib (inflammatory myofibroblastic tumor) or cediranib (alveolar soft part sarcoma), CDK4/6 inhibitors (liposarcoma), mTOR inhibitors such as nab-sirolimus (PEComa), epigenetic modifiers such as tazemetostat (epithelioid sarcoma), or immune checkpoint and/or angiogenesis modulators (alveolar soft part sarcoma). Not all subtype-specific explorations however led to successful Phase 3 trials, as illustrated by the failure of an antibody against endoglin (carotuximab) in angiosarcoma. The presentation will feature examples of relevant trials and highlight the complexity of drug development in STS.

ES03.04 Pegargiminase to Treat Mesothelioma

ES03.04 Pegargiminase to Treat Mesothelioma

1213P - Single intravenous preoperative administration of the oncolytic virus Pexa-Vec to prime anti-tumour immunity

BackgroundOncolytic viruses constitute a promising modality of cancer therapy. Pexa-Vec, a Thymidine Kinase-Deactivated Vaccinia Virus expressing GM-CSF, has been shown to target tumor tissue after intravenous (i.v.) administration (Breitbach C.J. et al., 2011). Herein, we report on the immunostimulatory effects of Pexa-Vec prior to surgical resection in patients with advanced solid tumors. MethodsPatients with operable tumors (3 with metastatic melanoma and 6 with colorectal cancer metastases to the liver (CRLM)) received a single i.v. dose of 1x109 plaque forming units of Pexa-Vec, approximately 14 days prior to surgical resection. Translational and histologic assessment was performed on blood samples collected pre- and post-injection and tumor collected at surgery. ResultsPexa-Vec injection was well tolerated in all cases. Pexa-Vec was detected in serum immediately after iv administration but not in PBMC. Histologic examination of tumor tissue indicates the presence of virus in tumor at the time of surgery 14 days after administration. Of the 4 evaluable CRLM, one showed complete necrosis, and another partial necrosis, within a normal background liver. Analysis of peripheral blood mononuclear cells and tumor infiltrating lymphocytes showed robust activation of Natural Killer (NK) cells and CD8+ cells, with high CD69 and PD-L1 expression. Functional assays revealed increased NK cell degranulation and elevated tumor-associated antigen recognition by T cells. Furthermore, Pexa-Vec induced a significant elevation of serum cytokines associated with immune response including IFNα, IFNβ, TRAIL and CXCL10. ConclusionsWhen administered intravenously, Pexa-Vec exhibited a selective persistence in tumor suggesting a tumor-targeted oncolytic action. Concurrently, Pexa-Vec triggered a robust immune activation of both innate and adaptive immune cells and infiltration of lymphocytes into tumor, associated with extensive necrosis in some patient tumours. These data strongly support the rationale for sequential i.v. use of oncolytic vaccinia virus in combination with immune checkpoint modulation therapy. Clinical trial identificationISRCTN13913966. Legal entity responsible for the studyUniversity of Leeds. FundingTransgene. DisclosureA. Samson: Research grant / Funding (institution): Transgene. K. Bendjama: Full / Part-time employment: Transgene. N. Stojkowitz: Full / Part-time employment: Transgene. M. Lusky: Full / Part-time employment: Transgene. A. Melcher: Research grant / Funding (institution): Transgene. F. Collinson: Research grant / Funding (institution): Transgene. All other authors have declared no conflicts of interest.

P04.19 Analysis of tumor immune microenvironment and immune checkpoint modulators across infantile and pediatric pilocytic astrocytomas to elucidate the role of immunotherapy in these tumors

Abstract BACKGROUND Pilocytic astrocytomas are the most common central nervous system tumors in pediatric age-group. Although grade I, some of the cases show recurrence and progression, and few might not be amenable to surgery due to location or size, and hence have a less favorable prognosis. Drugs blocking immune check-point interactions such as those including programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now in clinical use for certain tumors. We performed this study to understand the potential candidature of pilocytic astrocytomas in infants and children for immunotherapy by analyzing the expression of immune checkpoint proteins and immune infiltrate, and correlating with clinical details, wherever possible. MATERIALS AND METHODS Cases with adequate tissue (2010–2017) diagnosed in pediatric age-group (&lt;18 years) were retreived from the archives of Department of Pathology, AIIMS, New Delhi. Immunohistochemistry for PD-L1 (SP263, Ventana), CTLA-4, CD3, CD8, CD4 and CD68 was performed. Quantification of cytotoxic lymphocytes was done using digital imaging in the core of the tumor. RESULTS A total of 50 pilocytic astrocytomas were included, 14 of them were &lt;3 years (infants), while 36 were of pediatric age-group (3–18 years). Overall, male preponderance was noted. Cerebellum was the most common location, followed by 4th venrticle, optic pathway, hypothalamus, cerebrum and thalamus. Almost all CD3 lymphocytes were cytotoxic T-lymphocyes (CD8 positive, CTLs). Helper T-lymphocyte infiltration was not seen. Median CTL density/mm3 was 13/mm3(Range:1–85/mm3). CTLA-4 was positive in 4 cases, positivity ranged from 1–4 cells/lpf. PD-L1 was found to be positive in 7 cases, and the positivity ranged from 1+ to 2+ in 1 to 5% of tumor cells. A median TAM (tumor associated macrophages) density of 44/hpf (range: 1–98/hpf) was noted. There was no correlation of CTL density with PD-L1 or CTLA-4 expression, and neither with TAM density. On correlation with clinical parameters, a higher density of CTLs and TAMs was noted in infants, and a higher proportion of cases revealed PD-L1 positivity, though not statistically significant. There was no correlation of TILs or TAMs with the tumor location. CONCLUSION Immune check point blockade using PD-(L)1 or CTLA4 inhibitors may not be a potential therapeutic option for unresectable or recurrent pilocytic astrocytomas, as low positivity rate as well as extremely low percentage of tumor/ immune cells found to be positive. However, alternate forms of immunotherapy might be helpful as most of the cases showed immune infiltrates and a high density of tumor-associated macrophages (TAMs). Large scale studies with larger numbers and longer follow-up periods including in-vitro and clinical studies are warranted for decoding the tumor immunogram.

Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators.

A low response rate, acquired resistance and severe side effects have limited the clinical outcomes of immune checkpoint therapy. Here, we show that combining cancer nanovaccines with an anti-PD-1 antibody (αPD-1) for immunosuppression blockade and an anti-OX40 antibody (αOX40) for effector T-cell stimulation, expansion and survival can potentiate the efficacy of melanoma therapy. Prophylactic and therapeutic combination regimens of dendritic cell-targeted mannosylated nanovaccines with αPD-1/αOX40 demonstrate a synergism that stimulates T-cell infiltration into tumours at early treatment stages. However, this treatment at the therapeutic regimen does not result in an enhanced inhibition of tumour growth compared to αPD-1/αOX40 alone and is accompanied by an increased infiltration of myeloid-derived suppressor cells in tumours. Combining the double therapy with ibrutinib, a myeloid-derived suppressor cell inhibitor, leads to a remarkable tumour remission and prolonged survival in melanoma-bearing mice. The synergy between the mannosylated nanovaccines, ibrutinib and αPD-1/αOX40 provides essential insights to devise alternative regimens to improve the efficacy of immune checkpoint modulators in solid tumours by regulating the endogenous immune response.

Abstract 2816: SB1703 has therapeutic effect on syngeneic mouse model as an immune modulator in TME

Abstract Although stage I melanoma is highly curable, the prognosis of late stage melanoma is poor and treatment options are limited to immune checkpoint modulators (ICMs). In this study, we synthesized a novel small molecule, SB1703, and identified high-mobility group box (HMGB) proteins as the direct binding target proteins. SB1703 inhibited melanoma growth in B16F10 syngeneic mouse model. To elucidate the tumor growth inhibitory mechanism, we determined the changes in myeloid-derived suppressor cell (MDSC) number during drug treatment. MDSCs expand in disease states such as cancer and have immune suppressive functions. Serum HMGB1 and interleukin (IL)-6 levels were increased in vehicle administered mice and decreased in SB1703 administered mice. We examined the possibility of combinatorial treatment with SB1703 and ICMs. SB1703 showed synergistic effect with ICMs. In conclusion, SB1703 exhibited therapeutic effects against melanoma in both single and combination treatments with ICMs, which might be due to modulation of myeloid cells such as MDSCs Citation Format: Hyo Young Kim, Hee-Jung Kim, Jae Hoon Jung, So Young Jo, Ju Hee Kim, Wansang Cho, Mingi Kim, Junhyeong Yim, Seung Bum Park. SB1703 has therapeutic effect on syngeneic mouse model as an immune modulator in TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2816.

Abstract 2393: Bridging MOA-based reporter bioassays with PBMC based ADCC for immunotherapy drug development

Abstract Having a functional bioassay that is MOA-based, accurate, precise, robust and reproducible is critical for the development of antibody-based biologics. We have developed reporter bioassays that meet these criteria for a broad range of antibody modalities including Fc effector function, immune checkpoint modulation, bispecific antibody engagement, cytokine modulation, and others. Here we will present the latest technology advancements and bridging of the PBMC based ADCC cell killing assay with reporter based ADCC Bioassay. Citation Format: Mei Cong, Pete Stecha, Aileen paguio, brock binkowski, Zhi-Jie Cheng, Frank Fan. Bridging MOA-based reporter bioassays with PBMC based ADCC for immunotherapy drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2393.