scholarly journals IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC)

2021 ◽  
Vol 9 (8) ◽  
pp. e002903
Author(s):  
Russell K Pachynski ◽  
Chihiro Morishima ◽  
Russell Szmulewitz ◽  
Lauren Harshman ◽  
Leonard Appleman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Observation Group ◽  
Castration Resistant Prostate Cancer ◽  
Activation Markers ◽  
Castration Resistant ◽  
Ifn Γ ◽  
Over Time

BackgroundSipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP).MethodsFifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3H-thymidine incorporation, and ELISA.ResultsTreatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3–2.6-fold increases in CD4+T, CD8+T, and CD56bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group.ConclusionsTreatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.

Novel monoclonal antibody therapeutics for metastatic castration resistant prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14222-e14222
Author(s):  
Maloy Ghosh ◽  
Kavitha Iyer Rodrigues ◽  
Sunit Maity ◽  
Sanghamitra Bhattacharjee ◽  
Yogendra Manjunath ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Responses ◽  
Nk Cells ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Target Cells ◽  
Castration Resistant Prostate Cancer ◽  
Growth Reduction ◽  
Castration Resistant

e14222 Background: Therapeutic potential of innate immunity comprising Natural killer cell based targets are beginning to unravel the complexity of immune responses. NK cells recognize and induce cytotoxicity of wide range of target cells, such as, tumor cells without prior antigen sensitization. In this study, we have studied Lectin-like transcript 1 (LLT1), a member of the C-type lectin super family, is expressed on target cells and various immune cells. LLT1 isoform 1, is known to interact with CD161, a critical receptor on NK cells. CD161 is expressed on most of human NK cells, NK-T cells, γδ T cells and so on. Tumors exploit the CD161- LLT1 interaction to evade host defense mechanism (“DO NOT KILL” signal); indicating LLT1 as an attractive immunotherapeutic strategy. Methods: Prostate cancer cell lines and other tumor cell lines were used to evaluate novel anti LLT1 antibodies for therapeutic potential - IFNγ production assays and tumor cell death assays were carried out. In vivo efficacy of these antibodies were established using PC3 xenograft in humanized mouse model (HuNOG-EXL). Results: Human androgen independent prostate cancer cell line, PC3 was studied for LLT1 expression and interactions with immune cells, to understand role of LLT1 in metastatic castration resistant prostate cancer (mCRPC). Overexpression of LLT1 on tumor cells was influenced by cytokines and various TLRs. Inhibition of CD161-LLT1 interaction with novel anti LLT1 antibodies leads to IFNγ production and consequent NK cell mediated cytotoxicity – hall mark of anti-tumor responses. Disruption of LLT1 - CD161 innate immunity axis with anti LLT1 antibody releases the break on NK cell cytotoxicity and hence, established a new therapeutic option. PC3 xenograft on HuNOG mouse revealed in vivo efficacy of LLT1 antibody. Significant tumor growth reduction was observed with specific anti LLT1 antibodies alone and in combination with check point antibodies. Thus, synergistic tumor growth reduction was established by combinatorial application of anti LLT1 antibody and PD1/PDL1 axis inhibitors. Conclusions: PC3 xenograft study and other results point to therapeutic opportunities in metastatic castration resistant prostate cancer, a disease condition which needs improved patient outcomes. The ligation of CD161/LLT1 will serve as a new immuno-oncology pair regulating innate and adaptive immune responses; novel human antibodies against LLT1 described here will bring therapeutic benefit to patients in need.

scholarly journals Strategies for Optimizing the Clinical Impact of Immunotherapeutic Agents Such as Sipuleucel-T in Prostate Cancer

2012 ◽  
Vol 10 (12) ◽  
pp. 1505-1512 ◽  
Author(s):  
Ravi A. Madan ◽  
Thomas Schwaab ◽  
James L. Gulley
Keyword(s):  
Prostate Cancer ◽  
Immune Responses ◽  
Standard Of Care ◽  
Clinical Impact ◽  
Castration Resistant Prostate Cancer ◽  
Therapeutic Vaccines ◽  
Therapeutic Cancer Vaccine ◽  
Castration Resistant ◽  
New Strategies

Sipuleucel-T is a therapeutic cancer vaccine that has shown improved survival in men with metastatic castration-resistant prostate cancer. As a first-in-class agent, it has been met with both fan-fare and controversy. A broad review of immune-based therapies may reveal the delayed clinical impact of sipuleucel-T to be a class effect. As new strategies of immune-based therapy are developed, their effects can be optimized through better understanding of how they affect disease differently from more standard therapeutics. Furthermore, combination therapy with agents that can either work synergistically with immune-activating therapies or deplete immune-regulating cells may result in more vigorous immune responses and improved clinical outcomes. In addition, therapeutic vaccines may be ideal candidates to safely combine with standard-of-care therapies because of their nonoverlapping toxicity profile. The ultimate role of immunotherapy may not be to supplant standard therapies, but rather to work in concert with them to maximize clinical benefit for patients.

scholarly journals Oncogenic-Drivers Dictate Immune Responses to Control Disease Progression in Acute Myeloid Leukaemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 904-904
Author(s):  
Rebecca Austin ◽  
Megan Bywater ◽  
Jasmin Straube ◽  
Leanne T Cooper ◽  
Madeleine Headlam ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Research Funding ◽  
T Cell Subsets ◽  
Transcriptional Analysis ◽  
Immune Control ◽  
Immune Microenvironment ◽  
Ifn Γ

Abstract Immunotherapy has revolutionised therapeutic approaches to fight cancer and, in certain diseases dramatically improves survival. Clinical responses to immune checkpoint blockade have in part been attributed to high mutational burden of tumours such as melanoma. High-risk acute myeloid leukaemia (AML) is defined by molecular and cytogenetic factors. AML has a low prevalence of somatic mutations and is predicted to have low immunogenicity. We aimed to determine how AMLs driven from different classes of oncogenes interact with endogenous anti-leukemic immune responses. Methods and Results We generated three oncogenically distinct models of AML: BCR-ABL+NUP98-HOXA9 (BA/NH9), MLL-AF9 (MA9), and AML1-ETO+NRASG12D (AE/NRAS), using retroviral transduced bone marrow transplanted into immune-competent, non-irradiated C57BL/6J (B6) mice or immune-deficient Rag2-/-γc-/- mice. Immunologic control of AML was dependent on the driver oncogene, as AE/NRAS AML was effectively controlled in B6, but not Rag2-/-γc-/-recipients, whereas survival of BA/NH9 AML recipients was similar between B6 and Rag2-/-γc-/-. MA9 AML had an intermediate phenotype (Figure 1A-C). To examine the mechanisms underlying immune escape in AE/NRAS, AML from immune-deficient or immune-competent hosts, was passaged through immune-competent hosts. Prior exposure to an intact immune system dramatically accelerated disease progression of AE/NRAS AML in subsequent B6 recipients, but this was not seen in passage through Rag2-/-γc-/- recipients. This demonstrates specific, functional immunoediting of AML resulting in evasion of immune control. Despite evidence of disease attenuation in immune competent hosts, functional immunoediting was not observed in MA9 AML. Antibody-mediated immune cell depletion experiments demonstrated that natural killer (NK) cells and T cells both contribute to the control AE/NRAS AML, whereas MA9 immune control was dependent on NK cells. As immunoediting was only seen in AE/NRAS model, this suggests that functional immunoediting in this model is primarily mediated by T cells. To characterise the mechanisms regulating immunoediting, we integrated proteomic and transcriptional analysis of immunoedited and non-immunoedited AE/NRAS AML. There was strong correlation between increased protein expression and transcriptional regulation. There was distinct regulation of inflammatory pathways between immunoedited and non-immunoedited AML. Immunoedited AE/NRAS cells showed increased IFN-γ-dependent response signatures, consistent with direct targeting of the leukemic cells by the immune system. Transcriptional analysis also showed modulation of expression of immune checkpoint molecules including upregulation of suppressive molecules Tim-3 and CD39 and downregulation of activating ligand CD137L. These findings were confirmed by cell-surface flow cytometry. Immunoedited AE/NRAS downregulated RAS signalling transcriptionally, with coordinate activation of MYC targets. In the murine AE/NRAS model, CD4+ and CD8+ T effector memory (TEM) cells (CD44+ CD62L-) demonstrated increased PD-1 expression compared to naïve mice. In addition, mice with high disease burden also had increased frequency of T cells co-expressing exhaustion markers PD-1, Tim-3 and LAG-3, consistent with suppression of the anti-leukemic effector immune response. To understand if these findings were relevant to AML in the clinic, we obtained single cell RNA-sequencing data from the CD45+ CD34- non-leukemic fraction of bone marrow in a patient with AML1-ETO AML at diagnosis compared to that in normal marrow. Single cell type classification and clustering using tSNE demonstrated remodelling of the immune microenvironment in AML with loss of NK cells, pre-B cells and skewing of T cell subsets. There was depletion of CD8+ TEM cells and greater proportions of CD4+ and CD8+ TEM cells expressing activation and exhaustion markers (IFN-γ, PD-1, LAG-3, TIM-3). Conclusions These data demonstrate that immune responses in AML are oncogene-specific and provide evidence that AE/NRAS AML cells undergo immunoediting over time in the presence of a competent immune microenvironment. Since AML is associated with alterations in T cell subsets, and changes in T cell activation and exhaustion states, these findings may inform translational strategies to use immunotherapies for patients with AML. Disclosures Smyth: Bristol Myers Squibb: Other: Research agreement; Tizona Therapeutics: Research Funding. Lane:Janssen: Consultancy, Research Funding; Celgene: Consultancy; Novartis: Consultancy.

scholarly journals Relationship between Circulating Lipids and Cytokines in Metastatic Castration-Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4964
Author(s):  
Hui-Ming Lin ◽  
Nicole Yeung ◽  
Jordan F. Hastings ◽  
David R. Croucher ◽  
Kevin Huynh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Immune Responses ◽  
Treatment Response ◽  
Radiographic Progression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Baseline Levels ◽  
The Relationship ◽  
Cytokine Profiling

Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.

scholarly journals Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer

2020 ◽  
pp. 1167-1179
Author(s):  
David R. Wise ◽  
Jeffrey A. Schneider ◽  
Joshua Armenia ◽  
Victor Adorno Febles ◽  
Bridget McLaughlin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wnt Signaling ◽  
Nk Cells ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Dkk1 Expression ◽  
Rapid Autopsy ◽  
Dickkopf 1

PURPOSE Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)–expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies ( P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = −0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells ( P < .005) and lower numbers of activated NK cells ( P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353 ).

scholarly journals 340 Phase 1 study of AMG 160, a half-life extended BiTE® (bispecific T-cell engager) therapy targeting prostate-specific membrane antigen, in patients with metastatic castration-resistant prostate cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A365-A365
Author(s):  
Tanya Dorff ◽  
Matthew Rettig ◽  
Jean-Pascal Machiels ◽  
Martijn Lolkema ◽  
Karen Autio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Phase 1 ◽  
Castration Resistant Prostate Cancer ◽  
Phase 1 Study ◽  
Castration Resistant ◽  
Pet Ct ◽  
Specific Membrane

BackgroundProstate-specific membrane antigen (PSMA) is a clinically validated target for metastatic castration-resistant prostate cancer (mCRPC). AMG 160 BiTE® immuno-oncology therapy redirects T cells to cancer cells by binding to PSMA on cancer cells and CD3 on T cells, leading to T-cell activation, tumor-cell killing, and T-cell expansion. As the BiTE mode of action leads to an upregulation of immune checkpoints, combining AMG 160 with a PD-1 inhibitor may lead to sustained T cell–dependent killing of tumor cells. Cytokine release syndrome (CRS) is a first-dose effect induced by BiTE molecule-mediated T-cell activation. An approach to mitigate CRS is prophylaxis with an anti-inflammatory agent.MethodsThe phase 1 study (NCT03792841) has four parts: AMG 160 monotherapy; AMG 160 in combination with pembrolizumab; AMG 160 monotherapy with etanercept prophylaxis; and AMG 160 monotherapy administered in outpatient centers with 24-hour monitoring. Included in the study are men with histologically/cytologically confirmed mCRPC who are refractory to novel androgen receptor signaling inhibitors: abiraterone, enzalutamide, darolutamide, and/or apalutamide and have failed, refused, or are unsuitable for taxanes; and who have ongoing castration with evidence of progressive disease. Patients who received prior PSMA radionuclide therapy are eligible. Patients with CNS metastases, leptomeningeal disease, spinal cord compression, or active autoimmune disease are excluded. Primary objectives are to evaluate safety and tolerability and determine the MTD or RP2D of AMG 160 monotherapy or in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and preliminary antitumor activity. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, PSA response, CTC response, progression-free survival (radiographic and PSA), and overall survival. PSMA PET/CT and FDG PET/CT imaging will be used for evaluation of exploratory objectives (figure 1). The study opened in February 2019 and is currently recruiting patients.Abstract 340 Figure 1Study schemaResultsN/AConclusionsN/ATrial RegistrationNCT03792841Ethics ApprovalThe study was approved by all institutional ethics boards.

Randomized phase II study evaluating the addition of pembrolizumab to radium-223 in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 98-98
Author(s):  
Atish Dipankar Choudhury ◽  
Lucia Kwak ◽  
Alexander Cheung ◽  
Abhishek Tripathi ◽  
Amanda Fredericks Pace ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Cd8 T Cell ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Cell Infiltrate ◽  
Castration Resistant ◽  
Radium 223 ◽  
Pathologic Fractures ◽  
Bone Biopsies

98 Background: Treatment (tx) options for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) to bone are limited. Radium-223 (R223) has demonstrated overall survival (OS) benefit, but objective clinical responses to R223 or the anti-PD1 checkpoint inhibitor (CPI) pembrolizumab (pem) are infrequent. As R223 may increase immunogenicity of mCRPC to bone and increase activity of CPI, we undertook a Phase 2 study to assess safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of R223 + pem vs. R223 alone. Methods: Eligibility required mCRPC to bone with no visceral metastases (mets) or lymph nodes > 2 cm, ECOG PS 0 or 1, Hgb ≥ 9 g/dL, and no prior R223 or CPI. Pts underwent bone bx at screening and at 8 wks. Pts were stratified by alkaline phosphatase ≥220 vs. < 220 U/L and high vs. low volume bony mets (CHAARTED criteria) and randomized 2:1 to receive R223 55 kBq/kg q4wks + pem 200 mg q3wks (Arm A) or R223 55 kBq/kg q4wks alone (Arm B). If restaging after 3 doses R223 showed at least stable disease, pts in Arm A continued pem alone until progressive disease (PD). Upon PD, R223 was resumed if no new visceral mets. Pts continued tx until clinical/radiologic PD, unacceptable toxicity or completion of 6 R223 doses. The primary endpoint was difference in CD4+ and CD8+ T-cell infiltrate in 8 wk vs. baseline bx; secondary endpoints were safety/tolerability, radiographic progression-free survival (rPFS) and OS. Exploratory endpoints included PSA response and rate of symptomatic skeletal events (SSEs). Results: Of 45 pts enrolled, 42 received study tx (29 Arm A, 13 Arm B) and were eligible for analysis. 21 pts in Arm A and 5 in Arm B had evaluable paired bone bx. Median fold-change of proportion of CD4+ T-cells/total cell count from baseline to 8 wks was 0.90 (range 0.0-26.6) in Arm A and 0.40 (0.0-13.0) in Arm B (P = 0.87); for CD8+ cells, median 0.67 (0.0-40.4) in Arm A and 0.40 (0.1-28.8) in Arm B (P = 0.77). Grade 3 treatment-related non-hematologic adverse events (AEs) occurred in 3 pts (10%) in Arm A (pneumonitis, diarrhea, AST increased); none in Arm B. Median rPFS was 6.7 mo (95% CI 2.7-11.0 mo) in Arm A and 5.7 mo (2.6-NR) in Arm B. Median OS was 16.9 mo (12.7-NR) in Arm A and 16.0 mo (9.0-NR) in Arm B. 3 pts (10%) in Arm A and 0 in Arm B had PSA reduction of ≥ 50%. SSE rate was 38% in Arm A and 54% in Arm B, with pathologic fractures in 0% of pts in Arm A and 23% in Arm B. Conclusions: In the 62% of treated pts with evaluable paired bx at baseline and after 8 wks, there was no evidence of increased CD4+ or CD8+ T-cell infiltration with R223 + pem. Additional biomarker analyses will be presented. This study revealed that R233 + pem did not result in unexpected AEs, but did not lead to prolonged rPFS or OS compared to R223 alone to support this two-drug combination in a biomarker-unselected population in this setting. Clinical trial information: NCT03093428.

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