scholarly journals Efficacy and Safety of Durvalumab Combined with Daratumumab in Daratumumab-Refractory Multiple Myeloma Patients

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2452
Author(s):  
Kristine A. Frerichs ◽  
Christie P. M. Verkleij ◽  
Meletios A. Dimopoulos ◽  
Jhon A. Marin Soto ◽  
Sonja Zweegman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Single Agent ◽  
Efficacy And Safety ◽  
Immunomodulatory Effects ◽  
Serious Adverse Events ◽  
Blocking Antibody ◽  
Phase 2 Study

Daratumumab is active both as a single agent and in combination with other agents in multiple myeloma (MM) patients. However, the majority of patients will develop daratumumab-refractory disease, which carries a poor prognosis. Since daratumumab also has immunomodulatory effects, addition of the PD-L1 blocking antibody durvalumab at the time of progression may reverse daratumumab-resistance. The efficacy and safety of daratumumab and durvalumab in daratumumab-refractory relapsed/refractory MM patients was evaluated in this prospective, single-arm phase 2 study (NCT03000452). None of the 18 enrolled patients achieved PR or better. The frequency of serious adverse events was 38.9%, with one patient experiencing an immune related adverse event (grade 2 hyperthyroidism). No infusion-related reactions were observed. Analysis of tumor- and immune cell characteristics was performed on bone marrow samples obtained at baseline and during treatment. Daratumumab combined with durvalumab reduced the frequency of regulatory T-cells and decreased the proportion of T-cells expressing LAG3 and CD8+ T-cells expressing TIM-3, without altering T- and NK-cell frequencies. Durvalumab did not affect tumor cell characteristics associated with daratumumab resistance. In conclusion, the addition of durvalumab to daratumumab following development of daratumumab-resistance was associated with an acceptable toxicity profile, but was not effective. This indicates that inhibition of the PD-1/PD-L1 signaling pathway at the time of daratumumab-resistance is insufficient to reverse daratumumab-resistance.

scholarly journals Efficacy and Safety of Daratumumab Combined With All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma

2021 ◽  
Author(s):  
Kristine A. Frerichs ◽  
Monique Christina Minnema ◽  
Mark-David Levin ◽  
Annemiek Broijl ◽  
Gerard MJ Bos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stable Disease ◽  
Immune Cell ◽  
Ex Vivo ◽  
Phase 1 ◽  
Single Agent ◽  
Flow Cytometric Analysis ◽  
Optimal Dose ◽  
Efficacy And Safety ◽  
Cd38 Expression

The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. We have previously shown that ATRA upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy and safety of daratumumab combined with ATRA in daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR≥15%) was not met. However, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median PFS for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS, compared to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.

Impact of Lenalidomide Plus Low-Dose Dexamethasone Treatment on Immune Cell Populations of the Patients with Refractory/Relapsed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1769-1769
Author(s):  
Sung-Eun Lee ◽  
Ji-Young Lim ◽  
Da-Bin Ryu ◽  
Tae Woo Kim ◽  
Young-Woo Jeon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Partial Response ◽  
Low Dose ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Populations ◽  
Cell Frequency ◽  
Cd8 Cells ◽  
Cd8 Cell

Abstract Background: Lenalidomide combined with low-dose dexamethasone (Len-dex) is an effective treatment for the patients with refractory/relapsed multiple myeloma (RRMM). The anti-myeloma effect of lenalidomide is associated with activation of the immune system, but the exact immunomodulatory mechanisms in vivo and clinical impact of Len/dex in RRMM patients remains unclear. In this study, we analyzed immune cell populations in patients receiving Len-dex for the treatment of RRMM. Methods: Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len/dex therapy. CD3+, CD4+, CD8+, CD161+ T cells, natural killer (NK) cell (CD16+/CD56+), NKT-like cell (CD3+/CD56+) and myeloid-derived suppressor cell (MDSC) including granulocytic (G-MDSC) and monocytic (M-MDSC) were analyzed by flow cytometry. In addition, response was assessed in 81 patients receiving more than 4 cycles of Len-dex and the comparison of cell populations according to an achievement of ≥very good partial response (VGPR) was performed. Results: Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). At baseline, peripheral blood CD3+ cell frequency was 51.65 ± 1.79% which was significantly decreased to 41.67 ± 2.44% (P=0.001) and 39.72 ± 2.90% (P< 0.001) after 2 and 3 cycles of therapy, respectively. Frequency of both CD4+ cell and CD8+ cells was also significantly decreased by 3 cycles of therapy, while NK cell frequency was significantly increased after Len-dex treatment (P<0.05). For the T-cell subset, the frequency of CD8+ CD161high cells was significantly decreased (1.13 ± 0.16% at baseline to 0.65 ± 0.13% at post-3 cycles, P< 0.05), while no trend was observed in CD4+ CD161+ cell frequency. No significant change was observed in frequency of G-MDSC and M-MDSC after Len-dex. Among 81 evaluable patients, 36 patients obtained ≥VGPR and 45 ≤ partial response. After adjusting for factors affecting failure of achieving a response of ≥VGPR on univariate analyses, multivariate analyses showed that decrease in CD8+ cell frequency (P=0.043) and increase in M-MDSC frequency (P=0.033) by post-3 cycles of Len-dex treatment were predictors for failure of achieving ≥VGPR. High frequency of NKT-like cell prior to Len-dex treatment could predict a longer time to progression (RR of 0.40, P=0.011). In addition, patients with less decrease in frequency of both CD3+ cell and CD8+ cells by post-3 cycles had a longer time to next treatment (RR of 0.24, P=0.024 and RR of 0.33, P=0.044, respectively). Conclusion: Our data demonstrate that Len-dex therapy in patients with RRMM is associated with decreased frequency of T cells with a trend of increased NK cell frequency. Change in CD8+ cell and M-MDSC frequency can correlate with the quality of response to Len-dex. Baseline NKT-like cell frequency and change in CD3+ and CD8+ cells early after treatment may predict continuation of anti-myeloma effect of Len-dex therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunological Consequences of Lenalidomide with and without Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3070-3070
Author(s):  
Jake A. Kloeber ◽  
Teresa K. Kimlinger ◽  
Jessica L. Haug ◽  
Kimberly J. Henderson ◽  
S.Vincent Rajkumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Nk Cell ◽  
Single Agent ◽  
Cell Populations ◽  
Newly Diagnosed

Introduction: Recent advancements in the treatment of multiple myeloma (MM) have centered on engaging the immune system to target multiple myeloma cells. Although these therapies are being combined with immunomodulatory imide drugs (IMiDs) and corticosteroids, the individual contributions of these drugs on the immune system of MM patients has not been examined in the upfront setting. In this study, we examined the peripheral blood immunophenotypes of newly diagnosed multiple myeloma (NDMM) patients receiving the IMiD lenalidomide with or without the corticosteroid dexamethasone. Methods: To characterize immunophenotypes, we utilized flow cytometry to profile white blood cell populations from 35 patients enrolled in a clinical trial testing the efficacy of lenalidomide with and without dexamethasone in NDMM (NCT00772915). In this trial, all patients were initiated on single-agent lenalidomide. Dexamethasone was initiated in patients that did not meet desirable responses or for disease progression. At each cycle, peripheral blood was stained with a 17-marker antibody panel against several immune lineages and functional surface markers. We grouped patients into two groups: 1) lenalidomide alone or 2) lenalidomide with dexamethasone according to their treatment regimen at each cycle timepoint. Results: First we confirmed anti-myeloma cell activity for both groups by measuring a steady decline in circulating plasma cells in both groups. Examining peripheral blood immunophenotypes showed an expected decrease in T cells and a smaller decrease in B cells in both groups of patients. Closer inspection of B cell populations revealed a switch towards a more immature B cell phenotype in both treatment groups. This was measured as a switch from CD19-CD20+ cells to CD19+CD20- B cells. Inspection of T cell subsets revealed that patients receiving single-agent lenalidomide had a sustained decrease in the levels of CD4+ T cells and increase in the levels of CD8+ T cells. This was seen in both naïve and regulatory T cells evidenced by a decrease in the CD4/CD8 ratio among CD28+ T cells as well as CD25+ T cells. Importantly, this alteration did not lead to sustained alterations in the overall level of CD25+ or CD28+ T cells, and the addition of dexamethasone reverses this trend. In addition to the effects seen on T and B cell numbers, we detected expansions of NK cell populations in patients receiving lenalidomide alone. This expansion is detected as an overall increase in CD56+ mononuclear cells with the majority of cells being CD56+CD3- cells. Conclusions: Our data show that lenalidomide and dexamethasone therapy have shared but distinct effects on peripheral blood immunophenotypes in NDMM. Both drugs alter B cells numbers and populations leading to an expansion of CD19+CD20- B cells. However, lenalidomide alone decreases the CD4/CD8 T cell ratio; and, lenalidomide more strongly expands NK cell populations. The addition of dexamethasone reverses this trend and leads to a restoration of the CD4/CD8 ratio. This suggests that lenalidomide without dexamethasone might be counterproductive in immunotherapies intended to recruit CD4+ T cells. Conversely, lenalidomide alone could increase the efficacy of immunotherapies dependent on NK cell recruitment such as antibody-dependent cellular cytotoxicity (ADCC). This information may benefit future investigations of immune responses in MM patients and improve the adoption of immunotherapies to MM patients. Figure Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

scholarly journals 114 Preclinical development of a novel iPSC-derived CAR-MICA/B NK cell immunotherapy to overcome solid tumor escape from NKG2D-mediated mechanisms of recognition and killing

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A126-A126
Author(s):  
John Goulding ◽  
Mochtar Pribadi ◽  
Robert Blum ◽  
Wen-I Yeh ◽  
Yijia Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Immune Cell ◽  
Nk Cell ◽  
Tumor Escape ◽  
Car T Cells ◽  
Car T

BackgroundMHC class I related proteins A (MICA) and B (MICB) are induced by cellular stress and transformation, and their expression has been reported for many cancer types. NKG2D, an activating receptor expressed on natural killer (NK) and T cells, targets the membrane-distal domains of MICA/B, activating a potent cytotoxic response. However, advanced cancer cells frequently evade immune cell recognition by proteolytic shedding of the α1 and α2 domains of MICA/B, which can significantly reduce NKG2D function and the cytolytic activity.MethodsRecent publications have shown that therapeutic antibodies targeting the membrane-proximal α3 domain inhibited MICA/B shedding, resulting in a substantial increase in the cell surface density of MICA/B and restoration of immune cell-mediated tumor immunity.1 We have developed a novel chimeric antigen receptor (CAR) targeting the conserved α3 domain of MICA/B (CAR-MICA/B). Additionally, utilizing our proprietary induced pluripotent stem cell (iPSC) product platform, we have developed multiplexed engineered, iPSC-derived CAR-MICA/B NK (iNK) cells for off-the-shelf cancer immunotherapy.ResultsA screen of CAR spacer and ScFv orientations in primary T cells delineated MICA-specific in vitro activation and cytotoxicity as well as in vivo tumor control against MICA+ cancer cells. The novel CAR-MICA/B design was used to compare efficacy against NKG2D CAR T cells, an alternative MICA/B targeting strategy. CAR-MICA/B T cells showed superior cytotoxicity against melanoma, breast cancer, renal cell carcinoma, and lung cancer lines in vitro compared to primary NKG2D CAR T cells (p<0.01). Additionally, using an in vivo xenograft metastasis model, CAR-MICA/B T cells eliminated A2058 human melanoma metastases in the majority of the mice treated. In contrast, NKG2D CAR T cells were unable to control tumor growth or metastases. To translate CAR-MICA/B functionality into an off-the-shelf cancer immunotherapy, CAR-MICA/B was introduced into a clonal master engineered iPSC line to derive a multiplexed engineered, CAR-MICA/B iNK cell product candidate. Using a panel of tumor cell lines expressing MICA/B, CAR-MICA/B iNK cells displayed MICA specificity, resulting in enhanced cytokine production, degranulation, and cytotoxicity. Furthermore, in vivo NK cell cytotoxicity was evaluated using the B16-F10 melanoma cell line, engineered to express MICA. In this model, CAR-MICA/B iNK cells significantly reduced liver and lung metastases, compared to untreated controls, by 93% and 87% respectively.ConclusionsOngoing work is focused on extending these preclinical studies to further support the clinical translation of an off-the-shelf, CAR-MICA/B iNK cell cancer immunotherapy with the potential to overcome solid tumor escape from NKG2D-mediated mechanisms of recognition and killing.ReferenceFerrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, Tsoucas D, Franz B, May KF Jr, Harvey CJ, Kobold S, Pyrdol JW, Yoon C, Yuan GC, Hodi FS, Dranoff G, Wucherpfennig KW. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. Science 2018 Mar 30;359(6383):1537–1542.

scholarly journals 941 Stromal cell sialylation suppresses T cells in inflammatory tumour microenvironments: a new tumour stromal cell immune checkpoint?

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A987-A987
Author(s):  
Oliver Treacy ◽  
Hannah Egan ◽  
Kevin Lynch ◽  
Niamh Leonard ◽  
Kim De Veirman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Sialic Acid ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Immune Cell ◽  
Healthy Human ◽  
Human Donor ◽  
Healthy Human Donor

BackgroundImmunosuppressive tumour microenvironments (TME) reduce the effectiveness of immune responses in cancer. Non-haematopoietic mesenchymal stromal cells, precursors to cancer-associated fibroblasts (CAFs), dictate tumour progression by enhancing immune cell suppression. Sialic acids, which exist as terminal sugars of glycans (known as sialoglycans), are highly expressed on cancer cells and hyper-sialylation of glycans is known to promote immune evasion in cancer. Sialoglycans are recognized by sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of immunomodulatory receptors, which are analogous to the immune checkpoint inhibitor PD-1.1 The role of sialyation in stromal cell-mediated immunosuppression, however, is unknown. Using models of solid (colorectal cancer - CRC) and haematological (multiple myeloma - MM) stromal-rich tumours in both mouse and human, the aim of this study was to investigate if stromal cell sialylation contributes to enhanced immunosuppression in the TME.MethodsFlow cytometric analysis of sialic acid expression was performed initially on bone marrow-derived stromal cells isolated from healthy human donor bone marrow aspirates, from wild-type Balb/c mice or from 5T33 multiple myeloma mice. Stromal cells were also isolated and expanded from colorectal cancer patient tumour biopsies (CAFs) with matched controls isolated from tumour-adjacent non-cancerous tissue (normal-associated fibroblasts - NAFs) or from whole blood from primary multiple myeloma bone aspirates. Informed consent was obtained from all patients prior to sampling. Immunosuppression assays were performed using these stromal cells with or without exposure to the tumour cell secretome from the mouse and human CRC cell lines CT26 or HCT116 and HT29, respectively, co-cultured with either murine lymphocytes or healthy human donor-derived peripheral blood mononuclear cells (PBMCs).ResultsOur results showed that tumour conditioned stromal cells have increased levels of sialyltransferase gene expression, α2,3/α2,6-linked sialic acid and Siglec ligands. Co-culture assays revealed that CAFs induced significantly higher frequencies of Siglec 7 and Siglec 9-expressing CD8 T cells, as well as Tim-3 and PD-1-expressing CD8 T cells, compared to NAFs. Inhibition of sialyltransferase activity using the inhibitor 3FAXNeu5Ac reversed these CAF-induced effects. Interestingly, sialyltransferase inhibition had no observed effects on T cells co-cultured with NAFs.ConclusionsThese results demonstrate that targeting stromal cell sialylation can reverse immune cell suppression and reactivate exhausted T cells. These novel data support a rationale for the assessment of stromal cell sialylation and Siglec ligand expression in order to better stratify patients for immunotherapeutic combination treatments that aim to reactivate exhausted T cells in stromal-enriched tumour microenvironments.AcknowledgementsThe authors would like to thank the Blood Cancer Network of Ireland Biobank for providing bone marrow aspirates.ReferenceGray MA, Stanczak MA, Mantuano NR, Xiao H, Pijnenborg JFA, Malaker SA, Miller CL, Weidenbacher PA, Tanzo JT, Ahn G, Woods EC, Läubli H, Bertozzi CR. Targeted glycan degradation potentiates the anticancer immune response in vivo. Nat Chem Biol 2020;16:1376–1384.Ethics ApprovalColorectal tumor and adjacent normal mucosal tissue were obtained from patients undergoing colon tumor resection at University Hospital Galway under an ethically approved protocol (Clinical Research Ethics Committee, Ref: C.A. 2074). Samples were collected and isolated by the Blood Cancer Network of Ireland under an ethically approved protocol. Written informed explicit consent was obtained from all patients prior to sampling. Mice were housed and maintained following the conditions approved by the Animals Care Research Ethics Committee of the National University of Ireland, Galway (NUIG) and procedures were conducted under individual and project authorisation licenses from the Health Products Regulatory Authority (HPRA) of Ireland or from the Ethical Committee for Animal Experiments, Vrije Universiteit Brussel (license no. LA1230281, 16-281-6).

scholarly journals Tim-3 Induces Th2-Biased Immunity and Alternative Macrophage Activation during Schistosoma japonicum Infection

2015 ◽  
Vol 83 (8) ◽  
pp. 3074-3082 ◽  
Author(s):  
Nan Hou ◽  
Xianyu Piao ◽  
Shuai Liu ◽  
Chuang Wu ◽  
Qijun Chen
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Schistosoma Japonicum ◽  
Immune Cell ◽  
Nk Cell ◽  
Alternative Activation ◽  
Interleukin 12 ◽  
Content Type

T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected withSchistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response againstS. japonicuminfection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4+and CD8+T cells, NK1.1+cells, and CD11b+cells from the livers ofS. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8+T cells or CD11b+cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbersin vitroandin vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b+cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection.

scholarly journals ATIM-40. CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS PREDICT FAVORABLE RESPONSE TO IMMUNE CHECKPOINT THERAPY IN A RANDOMIZED TRIAL OF NIVOLUMAB AND BEVACIZUMAB IN RECURRENT GBM

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi10-vi10
Author(s):  
Manmeet Ahluwalia ◽  
Matthew Grabowski ◽  
Tyler Alban ◽  
Balint Otvos ◽  
Defne Bayik ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Suppressor Cells ◽  
Post Treatment ◽  
Myeloid Derived Suppressor Cells ◽  
Phase 2 Study ◽  
First Recurrence ◽  
Insight Into

Abstract Glioblastoma (GBM) creates an immunosuppressive environment that presents a challenge to efficacy of immunotherapeutic approaches. Results from the CheckMate-143 trial demonstrated responses in 8% of patients with nivolumab, underscoring the need for further insight into the mechanisms and markers of immune suppression and response. Given a limited set of biomarkers predictive of immunotherapy response in GBM, we explored the changes in immune cell populations in nivolumab and bevacizumab-treated GBM patients pre and post-treatment in order to help predict response. In these studies, we utilized traditional and newly developed approaches, including mass cytometry time-of-flight (CyTOF), single-cell RNA sequencing, and 10X Genomics simultaneous cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). We analyzed patients’ samples in a randomized, phase 2 study of nivolumab and bevacizumab at GBM first recurrence (NCT03452579). Nine patients were identified as responders or non-responders at 8 weeks after therapy initiation. Utilizing peripheral blood samples, we observed a 6.4-fold decrease in immunosuppressive myeloid-derived suppressor cells (MDSCs) between baseline and first imaging follow-up in responders compared to non-responders, with a 4.9-fold decrease in the granulocytic MDSC (G-MDSC) subtype in responders over non-responders. While no significant changes in overall T-cell numbers were noted, expression of PD-1 on CD4+ T cells was significantly elevated at baseline and follow-up in responders as compared to non-responders – signatures which were confirmed by CyTOF. Given these immunophenotypic changes, preliminary results of a detailed investigation of this cohort by CITE-seq indicate that responders had increased IL7R-positive T cells post-treatment, which was not observed in non-responders. These results are currently being validated in an additional 40 patients that have been enrolled. Altogether, differences in immunophenotypes that were specific to responders and non-responders were observed, and characterization of these immune populations may be helpful in identifying GBM patients likely to benefit from immunotherapy.

scholarly journals Identification of distinct immune activation profiles in adult humans

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Renaud Cezar ◽  
Audrey Winter ◽  
Delphine Desigaud ◽  
Manuela Pastore ◽  
Lucy Kundura ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
Liver Steatosis ◽  
Treg Cells ◽  
Microbial Translocation ◽  
Color Flow

AbstractLatent infectious agents, microbial translocation, some metabolites and immune cell subpopulations, as well as senescence modulate the level and quality of activation of our immune system. Here, we tested whether various in vivo immune activation profiles may be distinguished in a general population. We measured 43 markers of immune activation by 8-color flow cytometry and ELISA in 150 adults, and performed a double hierarchical clustering of biomarkers and volunteers. We identified five different immune activation profiles. Profile 1 had a high proportion of naïve T cells. By contrast, Profiles 2 and 3 had an elevated percentage of terminally differentiated and of senescent CD4+ T cells and CD8+ T cells, respectively. The fourth profile was characterized by NK cell activation, and the last profile, Profile 5, by a high proportion of monocytes. In search for etiologic factors that could determine these profiles, we observed a high frequency of naïve Treg cells in Profile 1, contrasting with a tendency to a low percentage of Treg cells in Profiles 2 and 3. Moreover, Profile 5 tended to have a high level of 16s ribosomal DNA, a direct marker of microbial translocation. These data are compatible with a model in which specific causes, as the frequency of Treg or the level of microbial translocation, shape specific profiles of immune activation. It will be of interest to analyze whether some of these profiles drive preferentially some morbidities known to be fueled by immune activation, as insulin resistance, atherothrombosis or liver steatosis.

A Phase I Trial Of Anti-KIR Monoclonal Antibody IPH2101 and Lenalidomide For Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3181-3181 ◽  
Author(s):  
Don M. Benson ◽  
Adam D Cohen ◽  
Craig C Hofmeister ◽  
Munshi C Nikhil ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Nk Cells ◽  
Nk Cell ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Low Grade ◽  
Dosing Interval ◽  
Infusion Reactions

Abstract Introduction Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy. MM utilizes specific immunoevasive strategies to avoid natural killer (NK) cell immune surveillance and cytotoxicity. Immunomodulatory agents such as lenalidomide (LEN) may exert indirect anti-MM efficacy via expansion and activation of NK cells. However, these favorable effects may be diminished when LEN is co-administered with high doses of dexamethasone (DEX). IPH2101 is a monoclonal anti-inhibitory KIR antibody which prevents negative signaling in NK cells and enhances NK cell recognition and killing of MM cells. A single-agent, phase I study of IPH2101 demonstrated full KIR blockade with encouraging safety and tolerability, and 34% of heavily pre-treated patients achieved disease stabilization (Blood 2012;120:4324-33). Preclinical data demonstrate that LEN and IPH2101 exert anti-MM effects via complementary NK-cell immunomodulatory mechanisms (Blood 2011;118:6397-91). Herein, data are presented from the first clinical experience with IPH2101 and LEN in combination in patients with MM. Methods A 3+3 phase I dose-escalation trial was conducted. Patients (age 18-80) with measurable, progressive MM were enrolled having received one or two prior lines of therapy. Prior LEN exposure was permitted unless resistance or intolerance was observed. Patients must have had ECOG performance status ≤ 2, creatinine clearance ≥ 60 ml/min, platelets ≥ 75,000/uL (or ≥ 30,000/uL if > 50% bone marrow plasma cells), absolute neutrophil count ≥ 1,000/uL, bilirubin < 1.5 ULN, and ALT / AST < 3 ULN. Patients must have adhered to standard prescribing guidelines for LEN. Three dose levels included: IPH2101 0.2mg/kg IV q 28 days + LEN 10 mg PO days 1-21; IPH2101 0.2 mg/kg + LEN 25 mg, and IPH2101 1mg/kg + LEN 25 mg for 4 cycles. Responding patients were allowed to receive 4 additional cycles. Patients completing all 8 cycles were maintained on LEN thereafter. No administration of DEX or other systemic corticosteroids was permitted. Dose reductions of LEN were permitted per prescribing information. The primary objective was to determine the safety and tolerability of IPH2101 + LEN, the secondary objectives included pharmacokinetics (PK) and pharmacodynamics (PD) of IPH2101 and biologic correlates with LEN as well as to determine clinical activity by standard IMWG uniform response criteria. Results 15 patients (10 M, 5 F, median age 60) were enrolled, 8 in first relapse and 9 in second relapse. 9 had prior LEN exposure. Cohorts 1 and 3 were expanded to n=6 patients respectively due to occurrence of possible dose-limiting toxicity. In both cases, a patient experienced a similar, apparent infusion reaction on cycle 1, day 1, characterized by fever, chills, cytokine release, and leucopenia. Events resolved with supportive care and both patients continued on trial without recurrence. The protocol was amended to include premedication with anti-histamine and acetaminophen,and no further infusion reactions were observed. Most other observed adverse events were of low grade and generally investigator-attributed as possibly or probably related to LEN. IPH2101 PD were not affected by co-administration of LEN. Full KIR occupancy was achieved in cohort 3 across the dosing interval. Five patients achieved a response (2 VGPR, 3 PR) with a median duration of 15+ months (3-26+). Conclusion The combination of IPH2101 + LEN appears to be a safe and well tolerated, and steroid-free combination in MM patients. Infusion reactions have not been observed since the addition of premedication prior to IPH2101 dosing. IPH2101 PD do not appear to be altered by co-administration of LEN, and full KIR blockade over the dosing interval has been achieved. Although the study is small, response rate and response duration are encouraging. These findings support further investigation of antiKIR therapy with LEN as the first, steroid-sparing, dual immunotherapy for MM. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without concomitant dexamethasone. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Caligiuri:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees.

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