Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate ...immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB.
Comprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient.
The median progression-free survival (PFS) for PHBR score < 0.5 vs. ≥ 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 mutations/mb, the stable disease > 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients.
Poor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective ...studies of anti–PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti–PD-1 antibody for post–alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti–PD-1 therapy post–alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT 01822509.
•This first prospective trial of PD-1 blockade for post–alloHCT relapse showed activity primarily in lymphoid malignancies.•Minimal activity was seen in myeloid malignancies, and GVHD and immune-related adverse events occurred.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells ...(LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors. In splicing reporter assays and pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. Therapeutic splicing modulation, together with monitoring splice isoform biomarkers of healthy HSPC aging versus LSC generation, may be employed safely and effectively to prevent relapse, the leading cause of leukemia-related mortality.
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•Splice isoform signatures distinguish normal and malignant progenitor cell aging•Pro-survival splice isoform switching is a feature of secondary AML LSC•Splice isoform biomarkers provide diagnostic and therapeutic targets for AML•Spliceosome modulators impair AML LSC maintenance in humanized pre-clinical models
Crews et al. show that unique splice isoform signatures distinguish normal human HSC and progenitor cell aging from AML and MDS progenitors. Widespread deregulation of splicing factor gene expression typified AML progenitors and sensitized them to small-molecule splicing-targeted agents, supporting the utility of spliceosome modulation in leukemia stem cell eradication and anti-aging strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that ...underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 antibody blocks growth of patient-derived AML, highlighting the importance of this pathway in human disease. These findings indicate that microenvironmental interactions are key regulators of AML and that disrupting these signals with targeted inhibitors such as CD98 antibodies may be a valuable therapeutic approach for adults and children with this disease.
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•Development and analysis of conditional CD98−/− model in the hematopoietic system•CD98 loss impairs propagation of established AML in mouse models of disease•Antibody-mediated CD98 blockade impairs primary human AML growth•CD98-mediated adhesion to vasculature promotes leukemia stem cell maintenance
Bajaj et al. demonstrate the importance of CD98-mediated adhesion for survival of acute myelogenous leukemia (AML) and show that genetic deletion of CD98 in mice or use of a therapeutic CD98 antibody in patient-derived xenografts blocks AML growth.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate ...to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Chronic graft versus host disease (chronic GVHD) still remains the leading cause of late morbidity and mortality for allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. In this ...retrospective study, 53 consecutive allo-HSCT patients with chronic GVHD refractory to corticosteroids were treated with extracorporeal photopheresis (ECP).
This study was performed as a retrospective single-center study. Medical records of a total of 59 patients treated with ECP for chronic GVHD were reviewed.
Best organ responses to ECP were observed in skin, mouth mucosa, eyes and liver. Overall response rate (ORR) to ECP was 81.2% (CR 17% and PR 64.2%). Overall survival (OS) was 84.9% and 36.7%, at 1 and 3 years, respectively. Female sex appears to have an advantage on ORR. Patients achieving ORR were able to maintain their responses with a prolonged continuation of treatments for +6 and +12 months indicating the benefits of longer ECP treatment.
We found that patients with chronic GVHD who were treated with ECP for 12 months or longer had a higher response rate. Our findings in line with the data reported previously suggest that patients responding to ECP should continue longer therapy schedules to achieve a better and sustained response. In our cohort, long-term ECP therapy was safe and well-tolerated with no significant adverse effects. Best responses were observed in the patients with skin, eye, liver and oral involvement. The ECP procedure offers the advantage relative to the problems with typical immunosuppressive agents. The female sex appeared to have an advantage based on the cumulative probability of the OR after ECP for chronic GVHD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Acute myeloid leukemia (AML) with the t(8;21)(q22;q22) chromosomal translocation is among the most common subtypes of AML and produces the
AML1-ETO
(
RUNX1-ETO
,
RUNX1-RUNX1T1
) ...oncogenic fusion gene. AML1-ETO functions as an aberrant transcription factor which plays a key role in blocking normal hematopoiesis. Thus, the expression of AML1-ETO is critical to t(8;21) AML leukemogenesis and maintenance. Post-transcriptional regulation of gene expression is often mediated through interactions between
trans
-factors and
cis
-elements within transcript 3′-untranslated regions (UTR).
AML1-ETO
uses the 3′UTR of the
ETO
gene, which is not normally expressed in hematopoietic cells. Therefore, the mechanisms regulating AML1-ETO expression via the 3’UTR are attractive therapeutic targets.
Methods
We used RNA-sequencing of t(8;21) patients and cell lines to examine the 3′UTR isoforms used by
AML1-ETO
transcripts. Using luciferase assay approaches, we test the relative contribution of 3′UTR
cis
elements to AML1-ETO expression. We further use let-7b microRNA mimics and anti-let-7b sponges for functional studies of t(8;21) AML cell lines.
Results
In this study, we examine the regulation of AML1-ETO via the 3’UTR. We demonstrate that
AML1
-
ETO
transcripts primarily use a 3.7 kb isoform of the
ETO
3′UTR in both t(8;21) patients and cell lines. We identify a negative regulatory element within the
AML1-ETO
3′UTR. We further demonstrate that the let-7b microRNA directly represses AML1-ETO through this site. Finally, we find that let-7b inhibits the proliferation of t(8;21) AML cell lines, rescues expression of AML1-ETO target genes, and promotes differentiation.
Conclusions
AML1-ETO is post-transcriptionally regulated by let-7b, which contributes to the leukemic phenotype of t(8;21) AML and may be important for t(8;21) leukemogenesis and maintenance.
Hematologic cancers that recur after allogeneic hematopoietic stem-cell transplantation are often difficult to treat. A small pilot study suggests that ipilimumab may induce durable responses in a ...subgroup of patients with these cancers.
Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only cure for many patients who have advanced hematologic cancers, principally through the induction of a graft-versus-tumor effect.
1
Unfortunately, more than one third of patients who have undergone transplantation have a relapse of disease.
2
The prognosis for these patients is poor; the majority die within 1 year after relapse despite salvage chemotherapy, donor-lymphocyte infusion, or retransplantation.
3
–
5
Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role.
6
The engagement of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed . . .
Treatment of acute myeloid leukemia (AML) has changed dramatically in the past ten years with the approval of targeted agents, the first of which was the anti-CD33 antibody-drug conjugate gemtuzumab ...ozogamicin (GO). Despite withdrawal from the market after accelerated approval, GO was reapproved and now has a well-established role in treating select AML patients. CD33 has proven to be an important target for drug development in AML as evidenced by the improvement in survival with GO treatment.
The review summarizes the development of GO, its mechanism of action, initial studies and approval, withdrawal from the market, and subsequent reapproval after the results of several large randomized studies became available. We also provide an overview of its current role in the treatment landscape of AML.
Multiple phase 3 trials with GO have established a significant benefit with GO in induction therapy for favorable risk AML. Additional studies support the use of GO in relapsed/refractory AML and APL. Despite the withdrawal of GO from the market after initial approval, GO has proven to improve survival of select AML patients when added to induction chemotherapy and in relapsed disease.
Background
To enhance donor availability, almost half of hematopoietic progenitor cell transplants (HPCTs) cross ABO blood type boundaries. ABO‐incompatible HPCTs are well tolerated; however, there ...is an increased risk of delayed hemolysis in patients with minor and bidirectional ABO mismatches. Delayed hemolysis generally occurs 1 to 2 weeks after HPCT and is related to production of alloantibodies directed against recipient ABO red blood cell (RBC) antigens by passenger donor lymphocytes. One previous study has suggested that prophylactic RBC exchange in patients with minor and bidirectional ABO‐mismatched HPCT reduces the risks of severe immune hemolysis, but this recommendation is controversial.
Study Design and Methods
Herein we describe our experience using prophylactic RBC exchange in patients with minor and bidirectional ABO‐mismatched HPCTs who were deemed to be at high risk for immune hemolysis. We compare the group of patients that received prophylactic RBC exchange with a historical cohort of ABO‐mismatched patients who underwent HPCT without prophylactic RBC exchange.
Results
Our study suggests that prophylactic RBC exchange in minor and bidirectional ABO‐mismatched HPCT does not reduce severe immune hemolysis, nor does it improve 1‐year survival, the number of RBC units transfused after transplant, or length of hospitalization after HPCT.
Conclusion
This study failed to identify a clear role for selected prophylactic RBC exchange in patients who were deemed at risk for severe post‐HPCT immune hemolysis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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