Presence of PD-1 Expressing T Cells Predicts for Inferior Overall Survival in Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1785-1785 ◽  
Author(s):  
Gasmi Billel ◽  
Eric L Smith ◽  
Ahmet Dogan ◽  
Meier Hsu ◽  
Sean Devlin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
P Value ◽  
Newly Diagnosed ◽  
Cell Infiltrate ◽  
Cell Exhaustion

Abstract Background: Programmed cell death 1 (PD-1) protein downregulates T cell activation and is related to immune tolerance. PDL1 up regulation, T cell infiltration, and T cell exhaustion are features, which suggest susceptibility to PD-1 blockade antibodies. Blockade of PD-1 or its ligand PD-L1 has shown promising responses in several malignancies. Although little clinical activity has been seen in patients with relapsed multiple myeloma (MM), the role of the PD-1 pathway and T cell exhaustion in newly diagnosed MM has not been explored. Objective: To determine whether T-cell infiltrate or expression of PD-1 correlates with clinical features and prognosis among patients with newly diagnosed multiple myeloma. Methods: We screened a clinically annotated database of 341 patients seen at MSKCC between 1998 and 2012 that had Multiple Myeloma, received a bone marrow transplant and were consented to a biospecimen research protocol for availability of pre-treatment bone marrow specimens. A total of 64 bone marrow biopsy specimens were identified. Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded specimens using an anti human CD3 monoclonal antibody (mAb) (Dako, Clone F7.2.38) and an anti human PD-1 mAb (Cell Marque, catalog #315M-95). CD3 and PD1 IHC staining were graded as negative (<5% for CD3, < 1% for PD1), or positive (≥5% for CD3, ≥1% for PD1). Correlative analyses were performed between CD3/PD1 expression and clinical outcome using the following parameters: International Staging System (ISS), cytogenetic risk, progression free survival (PFS), overall survival (OS), and response to treatment. Groups were compared by Fisher's exact test. OS and PFS were assessed by Cox regression and estimated by Kaplan-Meier methods. Results: 23 specimens (36%) were CD3 positive and 10 specimens (16%) were PD-1 positive. All PD-1 positive specimens were CD3 positive. 41 specimens (64%) were CD3 negative (<5%) and PD1 negative (<1%). Based on these results, specimens were divided into three groups: Exhausted T-cell infiltrate (CD3+/PD1+), non exhausted T-cell infiltrate (CD3+/PD1-) and no T-Cell infiltrate (CD3-/PD1-). In the exhausted T-cell infiltrate group 30% of patients had ISS stage 3 and 40% had high risk cytogenetics. In the non-exhausted T-cell group 15% of patients had ISS stage 3 and 15% high cytogenetic risk. In the no T-cell infiltrate group 10% had ISS stage 3 disease and 22% high cytogenetic risk. These proportions were not significantly different across the 3 groups. Median OS from 1st auto infusion was 7 years while median PFS was 2.3 years. On univariate analysis, there was no significant difference in PFS between the 3 groups. The presence of CD3 and PD1 T-cells were significantly associated with OS (p-value = 0.04). Median OS from 1st auto infusion was 43 months for the exhausted T-Cell infiltrate group followed by 83 months for the no T-Cell infiltrate group. The non exhausted T-cell group had the highest OS, median not reached; OS by 7-years was 75%. Cytogenetic risk at diagnosis was significantly associated with OS (p-value = 0.03). In a multivariable model, CD3/PD1 staining continued to trend toward an association with OS (p-value = 0.08) and cytogenetic risk remained significant (p-value = 0.05). Conclusions: The presence of T-cells with PD-1 expression was not associated with higher risk disease at MM diagnosis based on cytogenetics and ISS stage. The presence of PD-1 expressing CD3+ T cells trends toward an association with poorer overall survival in newly diagnosed MM, especially compared to non exhausted T-cell infiltrate, suggesting the possibility that T cell exhaustion represents a novel high risk disease characteristic. Further investigation is necessary to assess if the presence of CD3+PD-1+ T cells is an independent prognostic feature in newly diagnosed MM. Figure 1. Overall survival by CD3/PD1 Staining in 64 newly diagnosed myeloma patients. Figure 1. Overall survival by CD3/PD1 Staining in 64 newly diagnosed myeloma patients. Disclosures Giralt: JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding. Landgren:International Myeloma Foundation: Research Funding; Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Consultancy; BMJ Publishing: Consultancy; Celgene: Honoraria; Onyx: Honoraria; BMJ Publishing: Honoraria; Onyx: Research Funding. Hassoun:Novartis: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Efranat: Consultancy.

Increased Cytotoxic T-Cell Infiltrates in the Bone Marrow Is an Independent Adverse Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1492-1492
Author(s):  
Grzegorz S. Nowakowski ◽  
Chin-Yang Li ◽  
David Dingli ◽  
Shaji Kumar ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Prognostic Factor ◽  
Cytotoxic T Cells ◽  
Cytotoxic T Cell ◽  
Newly Diagnosed

Abstract Background: Cytotoxic T-cell infiltrates are a nearly universal finding in the bone marrow of patients with multiple myeloma. It has been postulated that presence of T-cells in the bone marrow of multiple myeloma (MM) patients represents an immune response against the tumor and therefore, might be associated with an improved prognosis. However, the impact of bone marrow T-cells on the prognosis of multiple myeloma patients has not been studied systematically. Methods: Bone marrow biopsies of patients with newly diagnosed multiple myeloma were stained by immnohistochemistry for the CD8 antigen and reviewed by a blinded hematopathologist. Three high power fields are reviewed for each biopsy and the total number of CD8 positive cells counted and reported. For patients with more than 300 cells per 3 fields, results were reported as &gt;300. The number of bone marrow CD8 positive cells was then correlated with patients’ clinical data, including other prognostic factors and overall survival. Results: Bone marrow biopsy specimens from 100 patients, performed within the week of a diagnosis of multiple myeloma and collected between May 1998 and January 2001 were evaluated. The median number of CD8 positive cells was 270 (33 – &gt;300). Patients’ characteristics are shown in Table 1. Median follow up was 30 months (0–80). The number of cytotoxic T-cells as a continuous variable was a risk factor for shortened overall survival, HR 1.86 (95% CI 1.11–3.35). Using minimal p value approach, the cutoff of 270 cells (the median) risk stratified patients into two groups: the median survival of patients with &gt; 270 CD8 positive cells was 16 months vs. 48 months in patients with ≤270 cells, p=0.005 (Figure). In multivariate analysis including age, B2M, albumin, CRP, bone marrow plasma cell percentage and plasma cell labeling index, the number of cytotoxic T-cells was an independent predictor of overall survival was HR 3.1, p=0.0017. Conclusion: We show that the number of cytotoxic T-cells in the bone marrow is a strong and independent prognostic factor in patients with newly diagnosed multiple myeloma. Our observation does not contradict the hypothesis that cytotoxic T-cells participate in an immune response against the tumor since our findings may represent a higher level of immune response associated with baseline aggressive disease biology. However, our study suggests for the first time that increased marrow cytotoxic T-cells have an adverse effect on outcome in myeloma, and suggest that these cells may have a direct facilitating effect on tumor growth and on the marrow microenvironment. Further studies of the biology of behind this observation are warranted. Characteristic N Median (range) Gender male 61 CRP 81 0.4mg/L (0.01–11.2) Albumin 99 3.6 g/dL (2.6–5.4) B2microglobulin 94 4.0 (0.9–28) μg/mL Marrow PC% 90 45% (11–99) PC labeling index 90 high (&gt;1%) 36 BM CD8 cells 100 270 (33 – &gt;300) ISS 94 1 19 2 41 3 34 Figure Figure

The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2016-2016
Author(s):  
Tomer M Mark ◽  
Peter Forsberg ◽  
Ihsane Ouansafi ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

T Cell Exhaustion and Downregulation of Cytotoxic NK Cells – an Immune Escape Mechanism in Adult Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3781-3781
Author(s):  
Eolia Brissot ◽  
Sawa Ito ◽  
Kit Lu ◽  
Carly Cantilena ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Research Funding ◽  
Immune Escape ◽  
Nk Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Healthy Donors

Abstract Adult acute lymphoblastic leukemia (ALL) remains a therapeutic challenge with less than 40% long term survival. There is growing evidence that malignant diseases exert an “immune editing” effect which blocks antitumor immunity and permits tumor growth through immune evasion. Such tumor escape represents an obstacle for anticancer immunotherapy. In ALL such immune escape mechanisms are not well characterized. We therefore profiled cellular immunity in ALL, by characterizing the subsets of T cells, regulatory T cells (Treg), natural killers (NK) cells and γd T cells, using various functional markers including T cell exhaustion and NK cell activating or inhibitory molecules. Forty ALL patients were included in the study. The median age was 39 y (range, 18-75). Thirty-six presented with B-lineage ALL and 4 with T-lineage ALL. Mononuclear cells were isolated from blood (n=19) or bone marrow (n=21) at the onset of leukemia or at relapse. The median infiltration of blasts was 85% (range 24-96%). Healthy donor peripheral blood (n=12) and bone marrow (n=9), from age and gender matched population, were simultaneously analyzed as controls. Extra-and intra cellular staining were performed using using antibodies directed against CD3, CD4, CD8, CD45, CD45, CD45RA, CD45RO, CCR7, CD95, CD27, CD19, CD14, CD127, CD25, Foxp3, Helios, αβTCR, HLA-DR, CD117, CD20, CD10, CD22, CD34, LAG3, PD1, PDL1, CD56, NKG2A, NKG2C, NKG2D, KIR2DL1, KIR2DL3, CD57, CD33, CD11b, CD15, CD38 and CD24. Data were acquired on a BD LSRFORTESSA flow cytometer. The expression of programmed cell death 1 (PD-1, CD279) receptor on CD8+T cells was significantly increased in blood and bone marrow of ALL patients compared to healthy donors (p<0.0001 and p=0.004, respectively) (Fig. 1). Focusing on the different subsets, CD8+ effector memory T cells significantly over-expressed PD-1 in blood and bone marrow of ALL patients compared to healthy donors (p=0.008 and p=0.04, respectively). Moreover, there was a significant positive correlation between PD-1 expression on CD8+ effector memory T cells and blast infiltration (R2=0.23, 95%CI 0.026-0.76, p=0.04). Expression of the co-inhibitory receptor lymphocyte-activation gene 3 (LAG-3, CD223) was similar in ALL patients compared to healthy donors. A significantly higher frequency of T regulators (CD25+, CD127 low, Foxp3+) was found in bone marrow microenvironment in ALL patients (4.3% versus 1.6%, p=0.02). Concerning γd T cells, frequency was similar in blood and bone marrow of ALL patients compared with healthy donors. There was a significantly lower frequency of CD56dimNKG2A+KIR-CD57- (p=0.02) in the bone marrow of ALL patients indicating a maturation arrest. Interestingly, expression of the activating receptor NKG2D which plays an important role in triggering the NK cell–mediated tumor cell lysis was significantly reduced in NK cells of ALL patients while no difference in NK cell expression of NKG2C was found(Fig. 2). Adult patients with ALL show evidence of immune-editing of T cells and NK cells. This global immunosuppressive mechanism may contribute to the eventual escape of ALL from immune control. PD-1, overexpression, described in acute myeloid leukemia and chronic myeloid leukemia has been implicated in T-cell exhaustion and subsequent tumor immune evasion. Our data suggests similar immune escape mechanisms pertain in ALL. Effective antileukemia immunotherapy will require targeting one or more of these immunosuppressive pathways to achieve optimum results. Disclosures Fathi: Seattle Genetics, Inc.: Consultancy, Research Funding; Takeda pharmaceuticals International Co.: Research Funding; Exelixis: Research Funding; Ariad: Consultancy.

scholarly journals Presence of Extrachromosomal DNA (ecDNA) Impacts Both Progression Free and Overall Survival and Is an Independent Poor Prognostic Marker in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 461-461
Author(s):  
Parth Shah ◽  
Anil Aktas-Samur ◽  
Mariateresa Fulciniti ◽  
Raphael Szalat ◽  
Masood A. Shammas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Copy Number ◽  
Research Funding ◽  
P Value ◽  
Newly Diagnosed ◽  
Extrachromosomal Dna ◽  
Publicly Traded ◽  
Advisory Committees

Abstract Background Focal amplifications and rearrangements drive tumor growth and evolution in cancer. Focally amplified regions often involve the juxtaposition of rearranged segments of DNA from distinct chromosomal loci into a single amplified region and nearly half of these regions can be explained by circular, extrachromosomal DNA (ecDNA) formation. Cancer-associated ecDNA shows a unique circular placing ecDNA at the interface of cancer genomics and epigenetics. As formation of ecDNA represents a manifestation of genomic instability, we have investigated presence and prognostic impact of ecDNA in multiple myeloma (MM). Methods Whole genome (WGS) and transcriptome (RNAseq) sequencing data from CD138 purified MM cells from 191 uniformly-treated newly diagnosed MM patients were used for this analysis. Copy number variants (CNV), single nucleotide variants (SNV) and structural variants (SV) were identified on all WGS samples using Facets, Mutect2 and Manta. Seed data from these CNV results was passed to the AmpliconArchitect tool to determine presence of focally amplified and rearranged segments of DNA. Seed CNV thresholds were set for a minimum CNV size of 100kb and a copy number of equal or greater to 5. Extrachromosomal calls were then annotated using the Amplicon Classifier to determine the presence of ecDNA. Multivariate survival analysis was performed after segregating samples into the conventional myeloma risk classifications including translocations, copy number alterations, ISS, age and mutations associated with risk. Differential expression analysis was performed on transcriptomic data using DEseq2. Results We identified 6.8% of the newly diagnosed patients with ecDNA, 12.5% with complex non-cyclic DNA amplifications and 10.1% with linear amplifications. ecDNA and complex events were targeting MM dependent genes, including MYC/PVT1, IRF4 as well as known driver genes such as CDYL and TRAF2. We further evaluated association between ecDNA, complex rearrangements, linear amplification and patients with none of these amplification types and found that patients with ecDNA had significantly poor PFS (median PFS 22 months vs. 41 months) and OS (median OS 41 months vs. 105 months). Patients having ecDNA in their MM cells did not show any significant enrichment for known translocations, double hit or TP53 mutations. In a multivariate model including ecDNA and all other known MM risk features, ecDNA was found to be an independent predictor of progression free survival.(HR 2.6, CI: 1.26 -5.6, p=0.0082) and overall survival (HR 7.94 CI:3.5-17.9 p &lt; 0.0001). Patients with ecDNA have higher mutational load probability(8798 vs 6982, effect size = 0.64 , probability is 91.1). However, this was not reflected in heterogeneity by using MATH score. We found that patients with ecDNA are likely to have BRAF mutations (OR= 25.07 [2.57 - 330 95% CI], p value = 0.002), however overall RAS/RAF pathway mutations were similar to other patients. Patients with ecDNA showed fragile DNA with more breaks (median segments 197 vs. 125.5, p value = 0.001). Although ecDNA is defined as copy number gain with fragments having 5 or more copies, overall genomic gain between ecDNA and other patients were similar. However, overall genomic loss in patients with ecDNA were higher than others (7% vs. 4.2%, p = 0.06). By differential gene expression analysis we noted 98 differentially expressed genes in MM cells with ecDNA. The downregulated geneset involved pathways responsible for cell death as well as the RAS pathway. Interestingly, CD38 was upregulated in the ecDNA dataset suggesting greater potential for CD38 targeting therapies in these patients. Conclusions ecDNA, as an unique marker of perturbed genomic integrity, is observed in a subset of patients and is an independent prognostic marker in newly diagnosed MM patients. As patients with ecDNA are not fully captured by other risk features its incorporation in an expanded definition of a high risk group of multiple myeloma should be investigated. Future studies will endeavor to explore the biological mechanism through which ecDNA are formed and influences outcomes in myeloma. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Secura Bio: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Thakurta: Oxford University: Other: Visiting Professor; BMS: Current Employment, Current equity holder in publicly-traded company. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Celgene: Consultancy; Pfizer: Consultancy.

scholarly journals Response-Adaptive Phase II Study of Daratumumab Combined with Carfilzomib, Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-39
Author(s):  
Manisha Bhutani ◽  
Monika House ◽  
Jiaxian He ◽  
Shebli Atrash ◽  
David M Foureau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Induction Therapy ◽  
Null Hypothesis ◽  
Research Funding ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Post Induction ◽  
Depth Of Response

Background Studies combining Daratumumab with a proteasome inhibitor and/ or an immunomodulatory drug have shown to increase the duration and depth of response in patients with newly diagnosed multiple myeloma (NDMM). While assessment of minimal residual status (MRD) after different stages of treatment is increasingly being evaluated in clinical trials as sensitive measure of depth of response and improved survival, published data on its utility as a tool to select the optimal post-induction therapy are not yet available. Study Design This ongoing single arm, two-stage, Phase II trial is designed with the primary objective to evaluate the efficacy in terms of rate of ≥ CR after 8 cycles of Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara + KRd) induction therapy in patients with NDMM. Induction treatment cycles consist of daratumumab per standard dosing, carfilzomib 56 mg/m2 IV days 1,8,15 (per latest amendment), lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. After induction, all subjects will undergo disease evaluation. Those who experience ≥very good partial response (VGPR) will undergo an assessment of MRD and will be classified as MRD(+) or MRD(-) as determined by next generation sequencing at 10-5 sensitivity (clonoSEQ®, Adaptive Biotechnologies), with further therapy guided by MRD-based algorithm (Figure). Those with &lt;VGPR will be considered to have MRD(+) disease and will follow MRD(+) algorithm. This trial will allow us to gather preliminary data on use of MRD status to direct post-induction therapy. Based on MRD status post-induction, patients will be divided into 3 separate groups: Group A: MRD(-) will be offered lenalidomide maintenance or no further treatment at the discretion of the investigator; Group B: MRD(+) eligible for transplant, will undergo autologous stem cell transplant (ASCT). Post ASCT, those who remain MRD(+) will receive up to 12 cycles of KRd; Group C: MRD(+) group, not eligible for transplant will receive up to 12 additional cycles of KRd. Study Population and Endpoints Eligible patients ≥ 18 years have NDMM requiring treatment, ECOG performance status 0-2, LVEF ≥45%, and creatinine clearance ≥ 30 mL/min. One prior cycle of systemic therapy is permitted to accommodate patients who needed emergent treatment at the time of diagnosis. Major exclusion criteria include non-secretory MM, active involvement of the central nervous system by MM, POEMS syndrome and severe COPD. Primary endpoint is CR or better after 8 cycles of Dara + KRd induction therapy. Secondary endpoints include PFS, OS, time to disease progression, overall response rate, duration of response, time to next treatment, and post-induction rate of MRD(-) response. Statistical Considerations A minimax 2-stage design will be used to test the hypothesis that the CR or better rate is ≤ 50%. Twenty-three subjects will be enrolled in the first stage, and if at least 12 of the 23 subjects have a CR or better after induction therapy, an additional 16 subjects will be enrolled (a total of 39 patients). If at least 24 of 39 subjects have a CR or better, the null hypothesis will be rejected. Based on a one-sided alpha = 0.10 significance level, this sample size will provide 90% power to reject the null hypothesis, assuming the true CR or better rate is 70%. Bayesian based stopping rules (Grade 3+ cardiovascular/pulmonary-related toxicities or any Grade 5 events) were developed that will be utilized for safety monitoring during induction phase of the study. Correlatives Beyond the direct anti-MM plasma cell activity, the Dara + KRd combination has a potent effect on immune effector cells and overall inflammation. Correlative aims include assessing blood and bone marrow immune biomarkers at baseline and during treatment for association with patient outcome. Mononuclear cells, isolated from peripheral blood samples and bone marrow aspirate will be obtained for NK, NKT, B and T cell immunotyping (including expression of activating/ inhibitory molecules and maturation status), T cell (αβ and γδ) clonotyping and chemokine-profiling. Additionally, MRD testing will be done by next generation flow cytometry (MRD-NGF) at 10-6 sensitivity. The study is actively recruiting at Levine Cancer Institute, Charlotte. At the time of submission, 8 subjects have enrolled and are in induction phase of treatment. Clinical trial information: ClinicalTrials.gov Identifier NCT04113018 Disclosures Bhutani: Janssen: Research Funding; BMS: Research Funding; MedImmune: Research Funding; Sanofi Genzyme: Consultancy. Atrash:Levine Cancer Institute, Atrium Health: Current Employment; Amgen, GSK, Karyopharm.: Research Funding; BMS, Jansen oncology, Sanofi: Speakers Bureau; Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria. Paul:Bristol-Myers Squibb: Other: Stock Ownership (prior employee); Regeneron: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau. Friend:Takeda: Speakers Bureau. Symanowski:Immatics: Consultancy; Casgen: Consultancy; Eli Lilly: Consultancy; Novartis: Consultancy. Voorhees:Oncopeptides: Honoraria, Other: Other relationship; Adaptive Biotechnologies: Honoraria, Other: Other relationship; TeneBio: Honoraria, Other: Other relationship; Janssen: Honoraria, Other: Other relationship; Novartis: Honoraria, Other: Other relationship; GSK: Honoraria, Other: Other relationship; BMS/Celgene: Honoraria, Other: Other relationship. Usmani:Celgene: Other; Array Biopharma: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; GSK: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding.

scholarly journals Adoptive Therapy with Cord Blood T Regulatory Cells Enhances Anti-Myeloma Efficacy of T Cell Based Immunotherapies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Mitsutaka Nishimoto ◽  
Li Li ◽  
Meixian Huang ◽  
Mi-Ae Lyu ◽  
Ke Zeng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cell ◽  
Tumor Growth ◽  
Cord Blood ◽  
Research Funding ◽  
Treg Cells ◽  
T Cell Exhaustion ◽  
Adoptive Therapy ◽  
Cell Exhaustion

Background. Inflammatory tumor microenvironment leads to T cell exhaustion in multiple myeloma leading to treatment failure and relapse. Specifically, T cell based therapies including bispecific antibodies and chimeric antigen receptor (CAR) T cell are associated with the additional side effects of non-specific T cell activation and cytokine release syndrome. Adoptive therapy with allogeneic cord blood (CB) T regulatory (Treg) cell therapy has been shown to be safe with clinical efficacy in a wide range of diseases including graft vs. host disease (GvHD), inflammatory bone marrow failures and COVID-19 induced acute respiratory distress syndrome. Furthermore, combination of Tregs with donor lymphocyte infusion (DLI) has led to resolution of leukemia relapse without GvHD flare up. We hypothesize that co-administration of Tregs with adoptive T cell based therapy will improve myeloma outcomes. Methods. 3x106 GFP-labeled MM.1S cells were injected into NSG mice followed by 5x106 CD3+ T conventional (Tcon) cells on day 14. In a subset of the Tcon treated mice, 1x107 CB Treg cells were injected on day 47, 54 and 61. Mice were followed every other day for weight and GvHD score. Non-invasive bioluminescent imaging (BLI) was performed serially. Weekly blood draw was performed for cell analysis and cytokine assays. At the time of euthanasia, blood, spleen and bone marrow were harvested for histopathology and flow analysis. In a subsequent experiment, intra-peritoneal injection of the bi-specific antibody against CD3 and BCMA (BCMA-BiTE) was administered in the xenogenic myeloma model in the presence or absence of CB Treg cells. Pan T cells were injected into all mice to facilitate the anti-tumor action of BiTE. Results. Both Tcon and Tcon+Treg recipients maintained their body weight compared to myeloma alone or myeloma + Treg arm (Figure A). All mice showed evidence of tumor growth by day 20 (Figure A). Widespread MM.1S cell growth in the myeloma only mice at day 27 was demonstrated by BLI whereas no measurable tumor growth was evident in Tcon recipients or Tcon+Treg recipients. By day 69, Tcon only mice were significantly increased tumor growth compared to Tcon+Treg recipients (Figure B). While circulating multiple myeloma cells were detected in myeloma alone and myeloma+Treg arm, no such evidence was detectable in the Tcon or Tcon+Treg recipients. However, upon euthanasia, extramedullary relapse of myeloma as retroperitoneal mass was detected in Tcon recipient (Figure C). Addition of Treg + BiTE led to a similar degree of tumor control compared to BiTE alone treated mice, however, a significant weight loss was observed in this arm (Figure D) with a corresponding high GvHD score (Figure E). Furthermore, addition of CB Treg cells led to decrease of T cell exhaustion phenotypic markers (data not shown). Conclusion. We are the first to show that CB Treg cells can be administered in combination with the T-cell based immunotherapies directed against myeloma. Such a strategy should be examined in the clinical setting. Figure Disclosures Nishimoto: Bayer Yakuhin, Ltd:: Research Funding; Janssen Pharmaceutical K.K.:: Research Funding. Sadeghi:Cellenkos Inc.: Current Employment. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Patel:Nektar: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

scholarly journals Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 815-815
Author(s):  
Farhad Ravandi ◽  
Naval Daver ◽  
Guillermo Garcia-Manero ◽  
Christopher B Benton ◽  
Philip A Thompson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
T Cell Subsets ◽  
Newly Diagnosed ◽  
Effector Cells ◽  
T Effector Cells ◽  
Grade 3

Abstract Background: Blocking PD-1/PD-L1 pathways enhances anti-leukemia responses by enabling T-cells in murine models of AML (Zhang et al, Blood 2009). PD-1 positive CD8 T-cells are increased in bone marrow (BM) of pts with AML (Daver et al, AACR 2016). PD1 inhibition has shown activity in AML (Berger et al, Clin Cancer Res 2008). We hypothesized that addition of nivolumab to an induction regimen of ara-C and idarubicin may prolong relapse-free survival (RFS) and overall survival (OS); this study was designed to determine the feasibility of this combination. Methods: Pts with newly diagnosed acute myeloid leukemia (by WHO criteria; ≥20% blasts) and high risk MDS (≥10% blasts) were eligible to participate if they were 18-65 yrs of age and had adequate performance status (ECOG ≤3) and organ function (LVEF ≥ 50%; creatinine ≤ 1.5 g mg/dL, bilirubin ≤ 1.5 mg/dL and transaminases ≤ 2.5 times upper limit of normal). Treatment included 1 or 2 induction cycles of ara-C 1.5 g/m2 over 24 hours (days 1-4) and Idarubicin 12 mg/m2 (days 1-3). Nivolumab 3 mg/kg was started on day 24 ± 2 days and was continued every 2 weeks for up to a year. For pts achieving complete response (CR) or CR with incomplete count recovery (CRi) up to 5 consolidation cycles of attenuated dose ara-C and idarubicin was administered at approximately monthly intervals. Eligible pts received an allogeneic stem cell transplant (alloSCT) at any time during the consolidation or thereafter. Results: 3 pts with relapsed AML were treated at a run-in phase with a dose of nivolumab 1 mg/kg without specific drug-related toxicity. Subsequently, 32 pts (median age 53 yrs; range, 26-65) were treated as above including 30 with AML (24 de novo AML, 2 therapy-related AML, 3 secondary AML and 1 therapy-related secondary AML) and 2 high risk MDS. Pre-treatment genetic risk by ELN criteria was 11 adverse, 16 intermediate, and 5 favorable, including 2 FLT3 -ITD mutated, 5 NPM1 mutated, and 7 TP53 mutated. All 32 pts were evaluable for response and 23 (72%) achieved CR/CRi (19 CR, 4 CRi). The 4-week and 8 week mortality was 6% and 6%. The median number of doses of nivolumab received was 6 (range, 0-13); one pt did not receive nivolumab due to insurance issues. 9 pts underwent an alloSCT. After a median follow-up of 8.3 mths (range, 1.5-17.0) the median RFS among the responding pts has not been reached (range, 0.1 - 15.8 mths) and the median OS has not been reached (range 0.5-17.0 mths). Grade 3/4 immune mediated toxicities have been observed in 5 pts and include rash, pancreatitis, and colitis. Other grade 3/4 toxicities thought to be potentially related to nivolumab include cholecystitis in one pt. 9 pts proceeded to an alloSCT. Donor source was matched related in 2, matched unrelated in 6 and haplo-identical in 1 pt. Conditioning regimen was Fludarabine plus busulfan-based in 8, and fludarabine plus melphalan in 1 pt. 4 pts developed graft versus host disease (GVHD)(grade I/II in 3, grade III/IV in 1), which responded to treatment in 3. Multicolor flow-cytometry studies are conducted by the Immunotherapy Platform on baseline (prior to first dose of nivolumab) and on-treatment BM aspirate and peripheral blood to assess the T-cell repertoire and expression of co-stimulatory receptors and ligands on T-cell subsets and leukemic blasts, respectively. The baseline BM was evaluated on 23 of the 32 evaluable pts, including 18 responders and 5 non-responders. Pts who achieved a CR/CRi had a trend of higher frequency of live CD3+ total T cell infiltrate as compared to non-responders in the baseline BM aspirates (Fig 1A). We evaluated expression of immune markers on T cell subsets: CD4 T effector cells [Teff]: CD3+CD4+CD127lo/+Foxp3-, CD4 T regulatory cells [Treg]: CD3+CD4+CD127-Foxp3+, and CD8 T cells. At baseline, BM of non-responders had significantly higher percentage of CD4 T effector cells co-expressing the inhibitory markers PD1 and TIM3 (p&lt;0.05) and a trend towards higher percentage of CD4 T effector cells co-expressing PD1 and LAG3 compared to responders (Fig 1B). Co-expression of TIM3 or LAG3 on PD1+ T cells have been shown to be associated with an exhausted immune phenotype in AML (Zhou et al., Blood 2011). Conclusion: Addition of nivolumab to ara-C and anthracycline induction chemotherapy is feasible and safe in younger pts with AML. Among the pts proceeding to alloSCT the risk of GVHD is not significantly increased. Figure 1 Figure 1. Disclosures Daver: Pfizer Inc.: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kiromic: Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Incyte Corporation: Honoraria, Research Funding. Thompson: Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jabbour: Bristol-Myers Squibb: Consultancy. Takahashi: Symbio Pharmaceuticals: Consultancy. DiNardo: Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sharma: Jounce: Consultancy, Other: stock, Patents & Royalties: Patent licensed to Jounce; Astellas: Consultancy; EMD Serono: Consultancy; Amgen: Consultancy; Astra Zeneca: Consultancy; GSK: Consultancy; Consetellation: Other: stock; Evelo: Consultancy, Other: stock; Neon: Consultancy, Other: stock; Kite Pharma: Consultancy, Other: stock; BMS: Consultancy. Cortes: BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding. Kantarjian: Delta-Fly Pharma: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding.

scholarly journals CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

Spontaneous CD4 and CD8 Memory T Cell Responses Against MUC1 and Carcinoembryonic Antigen in Bone Marrow of Multiple Myeloma Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3533-3533
Author(s):  
Mathias Witzens-Harig ◽  
Dirk Hose ◽  
Michael Hundemer ◽  
Simone Juenger ◽  
Anthony D. Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Carcinoembryonic Antigen ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses

Abstract Introduction: The bone marrow (BM) is a site of induction of tumour antigen specific T cell responses in many malignancies. We have demonstrated in the BM of myeloma patients high frequencies of spontaneously generated CD8 memory T cells with specificity for the myeloma-associated antigen MUC1, which were not detectable in the peripheral blood (PB). Besides MUC1, carcinoembryonic antigen was recently identified as a tumour-associated antigen in a patient with multiple myeloma. Up to now, spontaneous CD4 T cell responses against myeloma-associated antigens have not been reported. We undertook this study to evaluate to what extent spontaneous CD4 T cell responses against myeloma antigens occur during myeloma progression and if MUC1 or carcinoembryonic antigen represent immunogenic targets of spontaneous CD4 and CD8 T cell responses. Methods: Altogether, 78 patients with multiple myeloma were included into the study. Presence of functionally competent antigen specific T cells was evaluated by ex vivo short term (40 h) IFN-γ Elispot analyses. CD4 T cell responses against MUC1 were assessed by stimulation of purified CD4 T cell fractions with antigen pulsed, autologous dendritic cells (DCs) pulsed with two synthetic 100 meric polypeptides (pp1-100ss and (137–157)5 tr) that can be processed and presented via multiple HLA-II alleles. CD4- or CD8 T cell reactivity against carcinoembryonic antigen was assessed on purified CD4- and CD8 T cell fractions by pulsing DCs with highly purified CEA derived from culture supernatants of an epithelial carcinoma cell line. CD8 responses against MUC1 were analyzed by stimulation of HLA-A2+ patients derived purified T cells with DCs loaded with HLA-A2 restricted MUC1-derived nonameric peptide LLLLTVLTV. As negative control antigen for MUC1 polypeptides and CEA human IgG was used for pulsing DCs at identical concentrations while HLA-A2-restricted peptide SLYNTVATL derived from HIV was used as control antigen for LLLLTVLTV. Test antigen specific reactivity was defined by significantly increased numbers of IFN-γ spots in triplicate test wells compared to control wells (p<0.05, students T test). Results: 8 out of 19 tested patients (42%) contained MUC1 specific CD8 T cells in their bone marrow, while MUC1 specific CD4 T cells were detected in the BM of 30% of the cases (3/10). Interestingly, in peripheral blood (PB) CD8 reactivity against MUC1 was detectable in only 1 out of 10 patients while CD4 reactivity in PB was not detectable at all (0/10). CEA was specifically recognized by BM CD8 T cells from 5 out of 30 patients (17%) and by BM CD4 T cells from 5 out of 18 patients (28%). CEA was not recognized by CD4 and CD8 T cells in the PB of the same patients (0/13). Conclusion: Spontaneous T helper responses against tumour-associated antigens occur in the BM at similar levels as antigen specific CD8 T cells responses while they are virtually undetectable in the PB. Compared to CEA, MUC1 induces CD8 T cell responses in a much higher proportion of myeloma patients. Nevertheless, our data suggest that CEA may trigger spontaneous T cell responses against multiple myeloma in a considerable number of patients. Thus, systematic functional analyses of this potential tumour antigen in multiple myeloma appears to be justified.

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