Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study.

BACKGROUND: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome. METHODS: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 µg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621. FINDINGS: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient. INTERPRETATION: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions. FUNDING: Trillium Therapeutics.

Phase I Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. PATIENTS AND METHODS: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). RESULTS: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. CONCLUSIONS: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

TTI-621 (SIRPαFc), a CD47-blocking cancer immunotherapeutic, triggers phagocytosis of lymphoma cells by multiple polarized macrophage subsets.

Tumor-associated macrophages (TAMs) are heterogeneous and can adopt a spectrum of activation states between pro-inflammatory and pro-tumorigenic in response to the microenvironment. We have previously shown that TTI-621, a soluble SIRPαFc fusion protein that blocks the CD47 "do-not-eat" signal, promotes tumor cell phagocytosis by IFN-γ-primed macrophages. To assess the impact of CD47 blockade on diverse types of macrophages that are found within the tumor microenvironment, six different polarized human macrophage subsets (M(-), M(IFN-γ), M(IFN-γ+LPS), M(IL-4), M(HAGG+IL-1ß), M(IL-10 + TGFß)) with distinct cell surface markers and cytokine profiles were generated. Blockade of CD47 using TTI-621 significantly increased phagocytosis of lymphoma cells by all macrophage subsets, with M(IFN-γ), M(IFN-γ+LPS) and M(IL-10 + TGFß) macrophages having the highest phagocytic response. TTI-621-mediated phagocytosis involves macrophage expression of both the low- and high-affinity Fcγ receptors II (CD32) and I (CD64), respectively. Moreover, macrophages with lower phagocytic capabilities (M(-), M(IL-4), M(HAGG+IL-1ß)) could readily be re-polarized into highly phagocytic macrophages using various cytokines or TLR agonists. In line with the in vitro study, we further demonstrate that TTI-621 can trigger phagocytosis of tumor cells by diverse subsets of isolated mouse TAMs ex vivo. These data suggest that TTI-621 may be efficacious in triggering the destruction of cancer cells by a diverse population of TAMs found in vivo and support possible combination approaches to augment the activity of CD47 blockade.

TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.

Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails.Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068-79. ©2016 AACR.

[Maintenance treatment in opioid-dependent patients with migration background]. / Opioidsubstitution bei heroinabhängigen Patienten mit Migrationshintergrund.

BACKGROUND: No regional analyses regarding opioid-dependent patients in maintenance treatment with a migration background have so far been performed in German-speaking countries. OBJECTIVES: This study examined patients with and without a migration background regarding socioeconomic parameters, characteristics of dependency and attitude towards opiate maintenance treatment (OMT). MATERIAL AND METHODS: From May to October 2011 patients in OMT from all of the 20 psychiatry clinics and 110 physician practices in Berlin with a licence to provide OMT were included in this analysis. RESULTS: Out of the 986 participating patients, 956 gave information on migration background and of these, 204 (21.3 %) originated from a country other than Germany. Compared to patients without a migration background, their participation in a maintenance program was significantly shorter and they more often expressed a desire to end OMT and wanted a limited duration of OMT. CONCLUSION: The differences regarding duration of OMT and the wish to end OMT can reflect a stronger desire for abstinence and a different attitude towards maintenance treatment of patients with a migration background.

[Mental disorders of immigrants in Germany]. / Psychische Störungen bei Menschen mit Migrationshintergrund in Deutschland.

Currently the majority of data regarding indicators of psychiatric morbidity of migrant and minority groups in Germany is derived from studies on help-seeking behavior, mental health service use, or data from population studies, which were not specifically aimed at including migrants. Such data are only available for certain groups, for example, population-based studies on psychiatric disorders and suicidal behavior among Turkish migrants have been conducted, while, comprehensive data on the psychiatric morbidity among major migrant groups in Germany are still rather limited. Barriers to recruiting migrants for health studies, difficulties in assessing psychiatric morbidity in multi-cultural samples, observed as feasibility problems, are among the factors that interfere with population-based studies.

[Cross-cultural aspects of interaction and communication in mental health care. Barriers and recommendations for action]. / Interkulturelle Aspekte der Interaktion und Kommunikation im psychiatrisch/psychotherapeutischen Behandlungssetting. Mögliche Barrieren und Handlungsempfehlungen.

Mental health care for migrants is often impaired by a lack of policies and provisions in the respective institutions. This article focuses on "communication barriers" in psychosocial and psychotherapeutic settings, where personal communication is of great importance. Barriers that prevent migrants from using health care institutions include translation problems but also more complex misunderstandings based on divergent explanations regarding the causes, course, and adequate treatment of different disorders. The widely recommended intercultural opening of medical and psychosocial institutions involves using interpreters as cultural experts, reflecting on and mediating between divergent explanatory models, and avoiding cultural and ethnic stereotyping as well as encouraging an open, curious, and reflective professional attitude. With respect to institutional settings, rules for the financing of interpreters are as important as tackling barriers that limit migrants' access to medical and psychosocial institutions.

How to express mental health problems: Turkish immigrants in Berlin compared to native Germans in Berlin and Turks in Istanbul.

The paper explores expressions used by Turkish immigrants in Berlin to delineate psychiatric illnesses and psychological problems. These are compared to expressions used by native Germans in Berlin and Turks in Istanbul to assess possible cultural differences in articulating mental disorders. For this purpose, results of a Free Listing carried out with the three above mentioned groups are presented. The data suggest that relevant items which are connected to mental health issues vary between the groups as well as within the groups, thus showing dependency on factors such as education. For the group of Turkish immigrants the data further suggest that this group connects psychic stress to family problems. Concerning help seeking, Turkish immigrants, like members of the other groups, mention professional psychological/psychiatric help as useful for solving mental health problems.

The concept of "intercultural opening": the development of an assessment tool for the appraisal of its current implementation in the mental health care system.

The German concept of "intercultural opening" is an approach to facilitating migrants' access to the health care system and improving the care they receive. No data exist concerning the current status of the implementation of this approach in Germany, and the concept has never been analysed in practice. To assess the status of "intercultural opening" in the German mental health care system and to further analyse the concept, we developed a tool by combining pre-existing instruments. In order to review the preliminary tool we combined experts' knowledge by carrying out a consensusoriented, expert-based Delphi process with actual practice by piloting the instrument in each type of institution to be assessed. The assessment tool thus developed(1) is the first one to evaluate the current status of "intercultural opening" in the community mental health care system in Germany from a broad perspective. This paper is intended to present the development process of our assessment tool for demonstrating the benefits of this approach and as a model for future studies, as well as to increase transparency in relation to the current German approach to health care structures in dealing with migrants.

[Patients of immigrant origin in inpatient psychiatric facilities. Differences between first and second generation: nationwide questionnaire of the Psychiatry and Migration Working Group of the German Federal Conference of Psychiatric Hospital Directors]. / Patienten mit Migrationshintergrund in stationär-psychiatrischen Einrichtungen. Unterschiede zwischen erster und zweiter Generation: Bundesweite Umfrage der Arbeitsgruppe "Psychiatrie und Migration" der Bundesdirektorenkonferenz.

In a representative nationwide survey, the Psychiatry and Migration Working Group of the German Federal Conference of Psychiatric Hospital Directors examined the use of inpatient psychiatric and psychotherapeutic services in Germany by patients of immigrant origin. Questionnaires were sent to a total of 350 general hospital psychiatric clinics throughout Germany and 131 responded by the specified deadline (19 July 2006). In our study, persons of immigrant origin comprised 17% of patients in the responding facilities, which confirmed the results of the pilot study in 2004 of 17.4%. This indicates that the percentage of inpatient psychiatric services used by patients of immigrant origin is almost proportionate to these patients' percentage of the general population (18.6%, Microcensus 2005). In this main study patients of immigrant origin were significantly more likely to receive an ICD-10 F2 diagnosis, and it was precisely patients with this diagnosis who were observed to experience difficulties in communication with caregivers. With reference to the F2 diagnoses there were no noticeable differences between first generation of inpatients with migration history and second generation of inpatients with migration history. There were however more first generation of inpatients with migration history diagnosed with affective disorders whereas more second generation of inpatients with migration history were diagnosed with personality and behavioural disorders. Such differences were not found in the group of patients without immigrant origin. Whilst first generation of inpatients with migration history demonstrated higher educational levels, second generation of inpatients with migration history showed fewer linguistic difficulties.

Patients of immigrant origin in inpatient psychiatric facilities. A representative national survey by the Psychiatry and Migration Working Group of the German Federal Conference of Psychiatric Hospital Directors.

In a representative nationwide survey, the Psychiatry and Migration Working Group of the German Federal Conference of Psychiatric Hospital Directors (Bundesdirektorenkonferenz) examined the use of inpatient psychiatric and psychotherapeutic services in Germany by patients of immigrant origin. Questionnaires were sent to a total of 350 general hospital psychiatric clinics throughout Germany, and 131 clinics responded. As shown by the 2005 Microcensus [22], almost one-fifth (18.6%) of the German population is of immigrant origin. In our study, persons of immigrant origin comprised 17% of patients in the responding facilities. This indicates that the percentage of inpatient psychiatric services used by patients of immigrant origin is almost proportionate to these patients' percentage of the general population. The largest group of immigrant patients in our study were those of Russian heritage, followed by patients of Turkish, Arabic, or other origin. Almost two-thirds of the immigrant patients were born in Germany, and a considerably larger percentage were German citizens (74%). Sixty-two per cent of all patients of immigrant origin spoke a language other than German (e.g. Russian, Turkish, Polish) at home. Patients of immigrant origin were significantly more likely to receive an ICD-10 F2 diagnosis, and it was precisely patients with this diagnosis who were observed to experience difficulties in communication with caregivers.

Explanatory models of addictive behaviour among native German, Russian-German, and Turkish youth.

In Germany, the public system of addiction treatment is used less by migrants with addictive disorders than by their non-migrant counterparts. To date, the literature has focused primarily on language, sociocultural factors, and residence status when discussing access barriers to this part of the health care system. However, little attention has been paid to cultural differences in explanatory models of addictive behaviour. This is surprising when we consider the important role played by popular knowledge in a population's perceptions of and responses to illnesses, including their causes, symptoms, and treatment. In the present study, we examined explanatory models of addictive behaviour and of mental disorders in 124 native German und Russian-German youth and compared these models to those observed in an earlier study of 144 German and Turkish youth. We employed the free listing technique German and to compile the terms that participating subjects used to describe addictive behaviour. Subsequently, we examined how a subset of our study population assigned these terms to the respective disorders by means of the pile sort method. Although the explanatory models used by the German and Russian-German youth in our study were surprisingly similar, those employed by Turkish youth did not make any fundamental distinction between illegal and legal drugs (e.g. alcohol and nicotine). German and Russian-German youth regarded eating disorders as "embarrassing" or "disgraceful", but Turkish youth did not. Unlike our German and Russian-German subjects, the Turkish youth did not classify eating disorders as being addictive in nature. Moreover, medical concepts crucial to a proper understanding of dependence disorders (e.g. the term "physical dependence") were characterised by almost half of our Turkish subjects as useless in describing addictions. These findings show that it is impossible to translate medical or everyday concepts of disease and treatment properly into a different language without considering the connotations and implications of each term as it relates to the respective culture. Terms that are central to Western medical models of disease may otherwise be misunderstood, misinterpreted, or simply rejected.

Discovering novel phenotype-selective neurotrophic factors to treat neurodegenerative diseases.

Astrocytes and neurons in the central nervous system (CNS) interact functionally to mediate processes as diverse as neuroprotection, neurogenesis and synaptogenesis. Moreover, the interaction can be homotypic, implying that astrocyte-derived secreted molecules affect their adjacent neurons optimally vs remote neurons. Astrocytes produce neurotrophic and extracellular matrix molecules that affect neuronal growth, development and survival, synaptic development, stabilization and functioning, and neurogenesis. This new knowledge offers the opportunity of developing astrocyte-derived, secreted proteins as a new class of therapeutics specifically to treat diseases of the CNS. However, primary astrocytes proliferate slowly in vitro, and when induced to immortalize by genetic manipulation, tend to lose their phenotype. These problems have limited the development of astrocytes as sources of potential drug candidates. We have successfully developed a method to induce spontaneous immortalization of astrocytes. Gene expression analysis, karyotyping and activity profiling data show that these spontaneously immortalized type-1 astrocyte cell lines retain the properties of their primary parents. The method is generic, such that cell lines can be prepared from any region of the CNS. To date, a library of 70 cell lines from four regions of the CNS: ventral mesencephalon, striatum, cerebral cortex and hippocampus, has been created. A phenotype-selective neurotrophic factor for dopaminergic neurons has been discovered from one of the cell lines (VMCL1). This mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20 kD, glycosylated, human secreted protein. Homologs of this protein have been identified in 16 other species including C. elegans. These new developments offer the opportunity of creating a library of astrocyte-derived molecules, and developing the ones with the best therapeutic indices for clinical use.

[Different explanatory models for addictive behavior in Turkish and German youths in Germany: significance for prevention and treatment]. / Unterschiedliche Erklärungsmodelle für abhängiges Verhalten bei türkischen und deutschen Jugendlichen. Bedeutung für Prävention und Behandliungsangebote.

Due to cultural and social barriers, immigrants seldom frequent centers for information, counseling, and treatment of addictive disorders. We examine cultural differences in the explanatory models of addictive behavior among Turkish and German youths in Germany with statistical devices that map the concepts associated with problems of addiction. Relevant differences were found between the disorder concepts of Turkish and German youth. German but not Turkish youths classified eating disorders among severe addictive disorders and associated them with embarrassment and shame. Concerning substance abuse, German but not Turkish youths clearly differentiated between illegal drug abuse and the abuse of alcohol and nicotine. Nearly half of all Turkish youths rejected central medical concepts such as "physical dependence" or "reduced control of substance intake" as completely inadequate to characterize problems of addictive behavior. Preventive information programs must consider these differences and use concepts that are accepted and clearly associated with addictive behavior by immigrant populations.