Search

Primary effusion lymphoma (PEL) is an HIV-associated B-cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV). There is no validated prognostic model in PEL, and prognosis is thought to be poor compared to other HIV-associated NHL. We derived the PEL-Prognostic score (PEL-PS) from an international real-world training set of 59 patients with HIV-associated PEL who received first-line anthracycline-containing chemotherapy from the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI) in the United States and the National Center for HIV Malignancy at the Chelsea and Westminster Hospital (CWH) in England from 2000 to 2022. We identified prognostic factors associated with overall survival (OS). In a multivariable Cox model, ECOG ≥ 3 (p = 0.007; hazard ratio [HR] = 4.0 [95% CI: 1.5-11.1]) and hemoglobin < 8 g/dL (p = 0.006; HR = 3.8 [95% CI: 1.5-9.7]) were jointly associated with lower survival probability. The resulting PEL-PS separated patients with no negative prognostic factors (score 0: hemoglobin ≥ 8 g/dL and ECOG ≤ 2, 48.1% of patients) with median OS of 10.6 years versus patients with 1-2 negative prognostic factors (score 1-2: hemoglobin < 8 g/dL and/or ECOG ≥ 3, 51.9% of patients) with median OS of 0.8 years (p < 0.0001). The PEL-PS was then validated in 58 patients with HIV-associated PEL treated with first-line anthracycline-containing chemotherapy at Hôpital Saint-Louis in France over the same period: median OS in patients with PEL-PS 0 was 16.9 years versus 0.6 years in patients with PEL-PS score of 1-2 (p < 0.0001). The PEL-PS identifies patients with good and poor prognosis. Patients with poor prognosis may benefit from novel therapies., (© 2025 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: CD4 + T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS can contribute to increasing CD4 + T cell lymphocytopenia. IL-7 is a cytokine that is essential in T-cell development, proliferation and homeostasis. In PWH, IL-7 administration leads to increased numbers of circulating central memory and naïve T-cell phenotypes., Methods: In this multicenter phase I study with a 3+3 dose escalation design, participants with KS with or without HIV received up to four intramuscular injections of IL-7 (NT-I7) every 9 weeks. The primary endpoint of the study was to evaluate safety over three escalating dose levels (DL) of NT-I7 (DL1:480 µg/kg, DL2: 960 µg/kg and DL3: 1200 µg/kg) and identify a maximum tolerated dose. Secondary endpoints included evaluation of antitumor activity per the modified AIDS Clinical Trials Group Criteria and assessment of the effect of NT-I7 on the kinetics of CD4 + and CD8 + T-cells., Results: Eight cisgender male participants (five with HIV infection) were enrolled. Six participants were treated at DL1, and two were treated at DL2. The study was closed to accrual after enrolment of the second participant on DL2 due to termination of study funding. Four of the eight participants (three in DL1 and one in DL2) completed all four doses of the NT-I7. With regard to treatment-emergent adverse events (AEs), all participants had + and CD8 + T-cell counts increased among all participants following administration of NT-I7. Participants who experienced a response had HIV and lower CD4/CD8 ratio at baseline and throughout the study as compared with those who did not have KS response to NT-I7., Conclusions: Preliminary data demonstrate safety and activity of IL-7 in patients with KS and activity specifically among individuals HIV-associated KS., Trial Registration Number: NCT04893018., Competing Interests: Competing interests: RR, KL and RY report receiving research support from Celgene (now Bristol Myers Squibb), from CTI BioPharma (a Sobi Company), PDS Biotech, and Janssen Pharmaceuticals through CRADAs with the NCI. RR, KL and RY report receiving drug for a clinical trial from Merck through a CRADA with the NCI. RR, KL and RY report receiving drug for a clinical trial from EMD-Serano and Eli Lilly through a CRADA at the NCI. RY reports receiving preclinical material from Lentigen Technology through a CRADA or MTA with the NCI. MPM reports receiving research support from Roche through a CTA with Fred Hutchinson Cancer Research Center. TSU is currently employed by Regeneron Pharmaceuticals. TSU and RY are coinventors on US Patent 10,001,483 entitled 'Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers.' RY is also a coinventor on patents on a peptide vaccine for HIV and on the treatment of Kaposi sarcoma with IL12, and an immediate family member of RY is a coinventor on patents related to internalization of target receptors, on KSHV viral IL-6, and on the use of calreticulin and calreticulin fragments to inhibit angiogenesis. All rights, title, and interest to these patents have been or should by law be assigned to the US Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). No potential conflicts of interest were disclosed by the other authors. TSU name as a coinventor on US Provisional Patent Application 18/310,649, KSHV Oncoprotein Antigens and Epitodes for Expanding Antigen Specific T-cells., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

The clinical management of people with multidrug-resistant (MDR) human immunodeficiency virus (HIV) remains challenging despite continued development of antiretroviral agents. A 58-year-old male individual with MDR HIV and Kaposi sarcoma (KS) was treated with a new antiretroviral regimen consisting of anti-CD4 domain 1 antibody UB-421 and capsid inhibitor lenacapavir. The individual experienced delayed but sustained suppression of plasma viremia and a substantial increase in the CD4 + T cell count. A longitudinal examination of plasma HIV and infectious isolates showed no evidence of viral evolution or the emergence of UB-421- or lenacapavir-resistant viruses. The individual received three cycles of liposomal doxorubicin and five doses of anti-programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab that resulted in improvement in KS with flattening of lesions. Our data demonstrate that combination therapy with UB-421 could provide sustained virologic suppression in people harboring MDR HIV with limited therapeutic alternatives., Competing Interests: Competing interests: R.Y., R.R. and K.L. report receiving research support from Celgene (now Bristol-Myers Squibb), CTI BioPharma (a Sobi A.B. Company), PDS Biotech, and Janssen Pharmaceuticals, drugs for clinical trials from Merck, EMD-Serano and Eli Lilly, and preclinical material from Lentigen Technology through CRADAs or MTAs with the NCI. R.Y. is a co-inventor of US Patent 10,001,483 entitled ‘Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds and uses of biomarkers’. An immediate family member of R.Y. is a co-inventor on patents or patent applications related to internalization of target receptors, epigenetic analysis and ephrin tyrosine kinase inhibitors. All rights, title, and interest to these patents have been assigned to the U.S. Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). The other authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Abstract: Kaposi sarcoma herpesvirus (KSHV)-associated diseases include Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated multicentric Castleman disease (MCD), and KS inflammatory cytokine syndrome (KICS). PEL, MCD, and KICS are associated with elevated circulating inflammatory cytokines. However, activation of the inflammasome, which generates interleukin-1β (IL-1β) and IL-18 via active caspase-1/4/5, has not been evaluated in patients with KSHV-associated diseases (KADs). Herein we report that patients with HIV and ≥1 KAD present with higher plasma levels of IL-18 and increased caspase-1/4/5 activity in circulating monocytes compared with HIV-negative healthy volunteers (HVs) or people with HIV (PWH) without KAD. Within KAD subtypes, KICS and MCD shared enhanced caspase-1/4/5 activity and IL-18 production compared with HVs and PWH, whereas patients with PEL showed remarkably high levels of inflammasome complex formation (known as apoptosis-associated speck-like protein containing a caspase recruitment domain). Moreover, caspase-1/4/5 activity and IL-18 plasma levels correlated with KSHV viral load, indicating KSHV-driven inflammasome activation in KAD. Accordingly, factors released by cells latently infected with KSHV triggered inflammasome activation and cytokine production in bystander monocytes in vitro. Finally, both supervised and unsupervised analyses with inflammasome measurements and other inflammatory biomarkers demonstrate a unique inflammatory profile in patients with PEL, MCD, and KICS as compared with KS. Our data indicate that detrimental inflammation in patients with KAD is at least partially driven by KSHV-induced inflammasome activation in monocytes, thus offering novel approaches to diagnose and treat these complex disorders. These trials were registered at www.ClinicalTrials.gov as #NCT01419561, NCT00092222, NCT00006518, and NCT02147405., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Kaposi sarcoma (KS) is defined by aberrant angiogenesis driven by Kaposi sarcoma herpesvirus (KSHV)-infected spindle cells with endothelial characteristics. KS research is hindered by rapid loss of KSHV infection upon explant culture of tumor cells. Here, we establish patient-derived KS xenografts (PDXs) upon orthotopic implantation of cutaneous KS biopsies in immunodeficient mice. KS tumors were maintained in 27/28 PDX until experimental endpoint, up to 272 days in the first passage of recipient mice. KSHV latency associated nuclear antigen (LANA)+ endothelial cell density increased by a mean 4.3-fold in 14/15 PDX analyzed by IHC at passage 1 compared to respective input biopsies, regardless of implantation variables and clinical features of patients. The Ki-67 proliferation marker colocalized with LANA more frequently in PDXs. Spatial transcriptome analysis revealed increased expression of viral transcripts from latent and lytic gene classes in the PDX. The expanded KSHV+ regions of the PDX maintained signature gene expression of KS tumors, with enrichment in pathways associated with angiogenesis and endothelium development. Cells with characteristics of tumor-associated fibroblasts derived from PDX were propagated for 15 passages. These fibroblast-like cells were permissive for de novo KSHV infection, and one lineage produced CXCL12, a cancer-promoting chemokine. Spatial analysis revealed that fibroblasts are a likely source of CXCL12 signaling to CXCR4 that was upregulated in KS regions. The reproducible expansion of KSHV-infected endothelial cells in PDX from multiple donors and recapitulation of a KS tumor gene signature supports the application of patient-derived KS mouse models for studies of pathogenesis and novel therapies., Competing Interests: R. Yarchoan reports receiving research support from Celgene (now Bristol Myers Squibb), CTI BioPharma (a Sobi A.B. Company), PDS Biotech, and Janssen Pharmaceuticals through CRADAs with the NCI. Dr. Yarchoan also reports receiving drugs for clinical trials from Merck, EMD-Serano, and Eli Lilly and preclinical material from Lentigen Technology through CRADAs or MTAs with the NCI. R. Yarchoan is a co-inventor on US Patent 10,001,483 entitled “Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds and uses of biomarkers.” An immediate family member of R. Yarchoan is a co-inventor on patents or patent applications related to internalization of target receptors, epigenetic analysis, and ephrin tyrosine kinase inhibitors. All rights, title, and interest to these patents have been assigned to the U.S. Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502).

Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. These include near full-length sequence of genomes with KSHV K1 subtypes A, B, C, and F as well as subtype E, for which no full sequence was previously available. High levels of recombination were observed. Fourteen individuals (18%) showed evidence of infection with multiple KSHV variants (from two to four unique genomes). Twenty-six comparisons of sequences, obtained from various sampling sites including PBMC, tissue biopsies, oral fluids, and effusions in the same participants, identified near complete genome conservation between different biological compartments. Polymorphisms were identified in coding and non-coding regions, including indels in the K3 and K15 genes and sequence inversions here reported for the first time. One such polymorphism in KSHV ORF46, specific to the KSHV K1 subtype E2, encoded a mutation in the leucine loop extension of the uracil DNA glycosylase that results in alteration of biochemical functions of this protein. This confirms that KSHV sequence variations can have functional consequences warranting further investigation. This study represents the largest and most diverse analysis of KSHV genome sequences to date among individuals with KAD and provides important new information on global KSHV genomics., Competing Interests: R. Yarchoan reports receiving research support from Celgene (now Bristol Myers Squibb), CTI BioPharma (a Sobi A.B. Company), PDS Biotech, and Janssen Pharmaceuticals through CRADAs with the NCI. Dr. Yarchoan also reports receiving drugs for clinical trials from Merck, EMD-Serano, and Eli Lilly and preclinical material from Lentigen Technology through CRADAs or MTAs with the NCI. R. Yarchoan and T.S.Uldrick are co-inventors on US Patent 10,001,483 entitled "Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds and uses of biomarkers." An immediate family member of R. Yarchoan is a co-inventor on patents or patent applications related to internalization of target receptors, epigenetic analysis, and ephrin tyrosine kinase inhibitors. All rights, title, and interest to these patents have been assigned to the U.S. Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). Thomas Uldrick is also co-inventor on U.S. patent application no. 18/310,649, KSHV ONCOPROTEIN ANTIGENS AND EPITOPES FOR EXPANDING ANTIGEN-SPECIFIC T CELLS. Drs. Kathryn Lurain and Ramya Ramaswami receive research support from Bristol Myers Squibb, Merck, EMD-Serono, Eli Lilly, Lentigen, CTI BioPharma, and Janssen through CRADAs with the NCI. No potential conflicts of interest were disclosed by the other authors., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Kaposi sarcoma (KS) is a multicentric tumor caused by Kaposi sarcoma herpesvirus (KSHV) that leads to morbidity and mortality among people with HIV worldwide. KS commonly involves the skin but can occur in the gastrointestinal tract (GI) in severe cases., Methods: RNA sequencing was used to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions in 44 paired samples from 19 participants with KS alone or with concurrent KSHV-associated diseases. Analyses of KSHV expression from KS lesions identified transcriptionally active areas of the viral genome., Results: The transcript of an essential viral lytic gene, ORF75, was detected in 91% of KS lesions. Analyses of host genes identified 370 differentially expressed genes (DEGs) unique to skin KS and 58 DEGs unique to GI KS lesions as compared to normal tissue. Interleukin (IL)-6 and IL-10 gene expression were higher in skin lesions as compared to normal skin but not in GI KS lesions. Twenty-six cellular genes were differentially expressed in both skin and GI KS tissues: these included Fms-related tyrosine kinase 4 (FLT4), encoding an angiogenic receptor, and Stanniocalcin 1 (STC1), a secreted glycoprotein. FLT4 and STC1 were further investigated in functional studies using primary lymphatic endothelial cells (LECs). In these models, KSHV infection of LECs led to increased tubule formation that was impaired upon knock-down of STC1 or FLT4., Conclusions: This study of transcriptional profiling of KS tissue provides novel insights into the characteristics and pathogenesis of this unique virus-driven neoplasm., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10-22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara's effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL., Competing Interests: R. Yarchoan reports receiving drug supply for laboratory research from Janssen Pharmaceuticals and CTI BioPharma. R. Yarchoan, K. Lurain, and R. Ramaswami report receiving research support from Celgene (now Bristol Myers Squibb) through CRADAs with the NCI and receiving drugs for clinical trials from Merck, EMD-Serono, Eli Lilly, and Janssen through CRADAs with the NCI. R. Yarchoan is a co-inventor on US Patent 10,001,483 entitled “Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds and uses of biomarkers.” An immediate family member of R. Yarchoan is a co-inventor on patents or patent applications related to internalization of target receptors, epigenetic analysis, and ephrin tyrosine kinase inhibitors. All rights, title, and interest to these patents have been assigned to the U.S. Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). No potential conflicts of interest were disclosed by the other authors., (This work was authored as part of the Contributor’s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.)

Background: The Food and Drug Administration recommends that people living with HIV (PWH) with a CD4+ T cell count (CD4) ≥350 cells/µL may be eligible for any cancer clinical trial, but there is reluctance to enter patients with lower CD4 counts into cancer studies, including immune checkpoint inhibitor (ICI) studies. Patients with relapsed or refractory cancers may have low CD4 due to prior cancer therapies, irrespective of HIV status. It is unclear how baseline CD4 prior to ICI impacts the proportion of treatment-emergent adverse events (TEAE) and whether it differs by HIV status in ICI treated patients., Methods: We conducted a pilot retrospective cohort study of participants eligible for ICI for advanced cancers from three phase 1/2 trials in the USA and Spain. We determined whether baseline CD4 counts differed by HIV status and whether the effect of CD4 counts on incidence of TEAE was modified by HIV status using a multivariable logistic regression model., Results: Of 122 participants, 66 (54%) were PWH who received either pembrolizumab or durvalumab and 56 (46%) were HIV-negative who received bintrafusp alfa. Median CD4 at baseline was 320 cells/µL (IQR 210-495) among PWH and 356 cells/µL (IQR 260-470) among HIV-negative participants (p=0.5). Grade 3 or worse TEAE were recorded among 7/66 (11%) PWH compared with 7/56 (13%) among HIV-negative participants. When adjusted for prior therapies, age, sex, and race, the effect of baseline CD4 on incidence of TEAE was not modified by HIV status for any TEAE (interaction term p=0.7), or any grade ≥3 TEAE (interaction term p=0.1)., Conclusions: There was no significant difference in baseline CD4 or the proportions of any TEAE and grade ≥3 TEAE by HIV status. CD4 count thresholds for cancer clinical trials should be carefully reviewed to avoid unnecessarily excluding patients with HIV and cancer., Competing Interests: Competing interests: RR, TSU, KL, and RY report receiving research support from Celgene (now Bristol Myers Squibb) through a CRADA at the NCI. RR, TSU, KL, and RY report receiving drug for a clinical trial from Merck through a CRADA at the NCI. RR, KL, and RY report receiving drug for a clinical trial from EMD-Serono through a CRADA at the NCI. RY reports receiving drug for preclinical studies from Janssen and CTI BioPharma. TSU reports receiving other commercial research support from Roche through a CTA with Fred Hutchinson Cancer Center. JM-P reports receiving research support from AstraZeneca (through the Spanish Lung Cancer Group) and Merck. TSU and RY are coinventors on US Patent 10001483 entitled ‘Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers’. RY is also a coinventor on patents on a peptide vaccine for HIV and on the treatment of Kaposi sarcoma with IL-12, and an immediate family member of RY is a coinventor on patents related to internalization of target receptors, on KSHV viral IL-6, and on the use of calreticulin and calreticulin fragments to inhibit angiogenesis. All rights, title, and interest to these patents have been or should by law be assigned to the US Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). No potential conflicts of interest were disclosed by the other authors. TSU is currently an employee of Regeneron., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes., Patients and Methods: Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes., Results: Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%-87%. Twelve of 18 HIV-positive (67%; 95% CI, 41-87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%-97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6-15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases., Conclusions: Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV., (©2021 American Association for Cancer Research.)

Immunodeficiency, whether acquired in the case of human immunodeficiency virus (HIV) infection or congenital due to inborn errors of immunity (IEIs), presents clinically with not only infection and immune dysregulation but also increased risk of malignancy. The range of malignancies seen is relatively limited and attributable to the particular cellular and molecular defects in each disease. CD4+ T-cell lymphopenia in people living with HIV infection (PLWH) and certain IEIs drive the predisposition to aggressive B-cell non-Hodgkin lymphomas, including certain rare subtypes rarely seen in immunocompetent individuals. PLWH and IEI that lead to profound T-cell lymphopenia or dysfunction also are at risk of cancers related to oncogenic viruses such as Kaposi sarcoma herpesvirus, Epstein-Barr virus, human papillomavirus (HPV), and Merkel cell polyomavirus. IEIs that affect natural killer cell development and/or function heavily predispose to HPV-associated epithelial cancers. Defects in DNA repair pathways compromise T- and B-lymphocyte development during immune receptor rearrangement in addition to affecting hematopoietic and epithelial DNA damage responses, resulting in both hematologic and nonhematologic cancers. Treatment of cancers in immunodeficient individuals should be curative in intent and pursued in close consultation with disease experts in immunology and infectious disease.

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Background: Non-Hodgkin's lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control., Methods: We conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute., Results: We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1-21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2-3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide., Conclusions: Treatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL., Competing Interests: Competing interests: Pembrolizumab for NCT02595866 was provided to the NCI by Merck and Co. KL, RR, TSU and RY report research funding through Cooperative Research and Development Agreements (CRADAs) between Celgene Corporation (now Bristol Myers Squibb, Co) and the National Cancer Institute as well as a CRADA between EMD-Serrono and the National Cancer Institute. RY has also used drugs for his clinical or laboratory research provided to the NCI by Genentech Corp, EMD-Serono, Janssen Research, and CTI Biopharma. RY and TSU are co-inventors on US Patent 10,001,483 entitled 'Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers'. The patent application for this was filed in part based on the results of NCI protocol 12-C-0047, entitled 'A Phase I/II Study of the Safety, Pharmacokinetics and Efficacy of Pomalidomide (CC-4047) in the Treatment of Kaposi Sarcoma in Individuals with or without HIV'. It is their understanding that foreign patents have also been filed for this invention. This invention was made as full-time employees of the US government under 45 Code of Federal Regulations Part 7. RY’s spouse, who is also a US Government employee, has a patent on KSHV viral IL-6. All rights, title, and interest to these patents have been or should by law be assigned to the US Department of Health and Human Services. The government conveys a portion of the royalties it receives to its employee-inventors under the Federal Technology Transfer Act of 1986 (PL 99-502). TSU reports research funding to Fred Hutchinson Cancer Center from Roche and consulting fees (

Importance: Anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD1/PDL1) immune checkpoint blockade (ICB) constitutes the therapeutic backbone for multiple malignant neoplasms. People living with HIV (PLWH) have routinely been excluded from ICB clinical trials, thus inhibiting broad implementation of ICB to PLWH with cancer., Objective: To evaluate trends in the inclusion of PLWH in ICB cancer clinical trials that have occurred in association with ongoing efforts by the Cancer Therapy Evaluation Program (CTEP), National Cancer Institute, to promote inclusion of PLWH., Design, Setting, and Participants: This quality improvement study of ICB letters of intent (LOIs) included anti-PD1/PDL1 agents (nivolumab, pembrolizumab, atezolizumab, and durvalumab) submitted to CTEP that proceeded to approved protocols between January 2014 to May 2019. The setting was ICB clinical trial development and inclusion of underrepresented populations, specifically PLWH. All 97 submitted cancer clinical trial LOIs that included the aforementioned ICB agents were eligible for inclusion. Ten proposals were excluded, of which 3 were designed specifically for PLWH and 7 were LOIs that did not advance to approved protocols within the study period. Statistical analysis was performed from April to September 2020., Exposures: CTEP advocacy included the requirement for justification of exclusion of PLWH and formal discussion of inclusion criteria during conference calls between CTEP and trial investigators., Main Outcomes and Measures: The frequency of inclusion of PLWH in initially submitted LOIs was compared with final approved protocols using descriptive statistics. The probability of inclusion of PLWH in submitted LOIs and approved protocols over time was assessed using logistic regression., Results: Eighty-seven studies were included, of which 68 (78%) were pilot, phase 1, phase 1/2, or phase 2 studies and 19 (22%) were phase 2/3 or phase 3 studies. Thirty-nine studies (45%) included nivolumab, 23 (26%) included pembrolizumab, 19 (22%) included atezolizumab, and 6 (7%) included durvalumab. At initial LOI stage, 14 of 87 (16%) included PLWH. Following CTEP advocacy efforts, 61 of 87 protocols (70%) included PLWH. Of 36 LOIs to initially exclude PLWH, 24 (67%) included PLWH in final protocols. Among the 25 protocols to exclude PLWH, 21 (84%) were earlier phase studies (pilot to phase 2) and 4 (16%) were later phase studies (phase 2/3 to phase 3). Only 13 of 25 protocols (52%) provided justification for exclusion of PLWH, with safety being the most frequently cited concern (9 of 13 studies). The inclusion of PLWH on submitted LOIs increased over time (odds ratio, 3.38; 95% CI, 1.14-3.91), whereas inclusion on final protocols did not increase over time (odds ratio, 1.80; 95% CI, 0.81-1.59)., Conclusions and Relevance: This study identified encouraging trends in the inclusion of PLWH in anti-PD1/PDL1 cancer trials that occurred in the period following the initiation of CTEP advocacy. Work is needed to examine what impact this will have on enrollment of PLWH in such trials. Similar advocacy may help to promote inclusion of other underrepresented populations in cancer clinical trials, including those with organ dysfunction and chronic infections.

Kaposi sarcoma herpesvirus (KSHV) is the etiological agent of three malignancies, Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and KSHV-associated multicentric Castelman disease. KSHV infected patients may also have an interleukin six-related KSHV-associated inflammatory cytokine syndrome. KSHV-associated diseases occur in only a minority of chronically KSHV-infected individuals and often in the setting of immunosuppression. Mechanisms by which KSHV genomic variations and systemic co-infections may affect the pathogenic pathways potentially leading to these diseases have not been well characterized in vivo . To date, the majority of comparative genetic analyses of KSHV have been focused on a few regions scattered across the viral genome. We used next-generation sequencing techniques to investigate the taxonomic groupings of viruses from malignant effusion samples from fourteen participants with advanced KSHV-related malignancies, including twelve with PEL and two with KS and elevated KSHV viral load in effusions. The genomic diversity and evolutionary characteristics of nine isolated, near full-length KSHV genomes revealed extensive evidence of mosaic patterns across all these genomes. Further, our comprehensive NGS analysis allowed the identification of two distinct KSHV genome sequences in one individual, consistent with a dual infection. Overall, our results provide significant evidence for the contribution of KSHV phylogenomics to the origin of KSHV subtypes. This report points to a wider scope of studies to establish genome-wide patterns of sequence diversity and define the possible pathogenic role of sequence variations in KSHV-infected individuals., (Published by Oxford University Press 2020. This work is written by US Government employees and is in the public domain in the US.)

Purpose: VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma., Patients and Methods: Patients with Kaposi sarcoma requiring systemic therapy were enrolled in one of two cohorts. Cohort 1 included patients with human immunodeficiency virus (HIV)-negative Kaposi sarcoma or with HIV-associated Kaposi sarcoma who would not be expected to respond to antiretroviral therapy (ART) alone (i.e., either stable or progressive Kaposi sarcoma on ART). Cohort 2 included all other patients with HIV-associated Kaposi sarcoma. Patients were treated with six cycles of liposomal doxorubicin with bevacizumab every 3 weeks followed by up to 11 cycles of bevacizumab alone., Results: Sixteen patients were enrolled: 10 (two HIV negative) in cohort 1 and six in cohort 2. Fourteen patients had advanced disease (AIDS Clinical Trials Group T 1 ). Overall response rate (complete and partial responses) was 56% [80% confidence interval (CI), 38%-74%] for all patients and were similar in the two cohorts. Median progression-free survival was 6.9 months (95% CI, 4.5 months-not estimable). Grade 3 and 4 adverse events attributed to therapy included hypertension ( n = 5), neutropenia ( n = 6), gastrointestinal hemorrhage ( n = 1), and cerebral ischemia ( n = 1). There was a significant decrease in VEGF-A levels from baseline to the end of six cycles of combination therapy., Conclusions: Pegylated liposomal doxorubicin in combination with bevacizumab has activity in advanced Kaposi sarcoma, but it is unclear whether the combination yields better outcomes than liposomal doxorubicin used alone., (©2019 American Association for Cancer Research.)

Primary effusion lymphoma (PEL) is an aggressive HIV-associated lymphoma with a relatively poor prognosis in the era of effective HIV therapy. Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent, and ∼80% of tumors are coinfected with Epstein-Barr virus (EBV). A better understanding of how KSHV-related immune dysregulation contributes to the natural history of PEL will improve outcomes. Twenty patients with PEL diagnosed between 2000 and 2013, including 19 treated with modified infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (EPOCH), were identified. We compared their clinical, virologic, and immunologic features vs 20 patients with HIV-associated diffuse large B-cell lymphoma and 19 patients with symptomatic interleukin (IL)-6 related KSHV-associated multicentric Castleman disease. Survival analyses of treated patients with PEL were then performed to identify prognostic factors and cancer-specific mortality. Compared with HIV-associated diffuse large B-cell lymphoma, PEL was associated with significant hypoalbuminemia ( P < .0027), thrombocytopenia ( P = .0045), and elevated IL-10 levels ( P < .0001). There were no significant differences in these parameters between PEL and KSHV-associated multicentric Castleman disease. Median overall survival in treated patients with PEL was 22 months, with a plateau in survival noted after 2 years. Three-year cancer-specific survival was 47%. EBV-positive tumor status was associated with improved survival (hazard ratio, 0.27; P = .038), and elevated IL-6 level was associated with inferior survival (hazard ratio, 6.1; P = .024). Our analysis shows that IL-6 and IL-10 levels contribute to the natural history of PEL. Inflammatory cytokines and tumor EBV status are the strongest prognostic factors. Pathogenesis-directed first-line regimens are needed to improve overall survival in PEL., (© 2019 by The American Society of Hematology.)

Noncoding RNAs have substantial effects in host-virus interactions. Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs which can decoy other RNAs or RNA-binding proteins to inhibit their functions. The role of circRNAs is largely unknown in the context of Kaposi's sarcoma herpesvirus (KSHV). We hypothesized that circRNAs influence viral infection by inhibiting host and/or viral factors. Transcriptome analysis of KSHV-infected primary endothelial cells and a B cell line identified human circRNAs that are differentially regulated upon infection. We confirmed the expression changes with divergent PCR primers and RNase R treatment of specific circRNAs. Ectopic expression of hsa&#95;circ&#95;0001400, a circRNA induced by infection, suppressed expression of key viral latent gene LANA and lytic gene RTA in KSHV de novo infections. Since human herpesviruses express noncoding RNAs like microRNAs, we searched for viral circRNAs encoded in the KSHV genome. We performed circRNA-Seq analysis with RNase R-treated, circRNA-enriched RNA from KSHV-infected cells. We identified multiple circRNAs encoded by the KSHV genome that are expressed in KSHV-infected endothelial cells and primary effusion lymphoma (PEL) cells. The KSHV circRNAs are located within ORFs of viral lytic genes, are up-regulated upon the induction of the lytic cycle, and alter cell growth. Viral circRNAs were also detected in lymph nodes from patients of KSHV-driven diseases such as PEL, Kaposi's sarcoma, and multicentric Castleman's disease. We revealed new host-virus interactions of circRNAs: human antiviral circRNAs are activated in response to KSHV infection, and viral circRNA expression is induced in the lytic phase of infection., Competing Interests: Conflict of interest statement: T.S.U. is a coinventor on a patent application related to the treatment of KSHV-associated diseases with pomalidomide. This invention was made as part of his duties as an employee of the US government, and the patents are or will be assigned to the US Department of Health and Human Services. The government may convey a portion of the royalties it receives from licensure of its patents to its employee inventors. T.S.U. has recently conducted clinical research using drugs supplied to the National Cancer Institute through cooperative research and development agreements with Celgene Corp., Merck and Co., and Hoffman LaRoche.

Corticosteroid use was associated with development of Kaposi's sarcoma or multicentric Castleman disease in 3 patients with mycobacterial immune reconstitution inflammatory syndrome (IRIS) treated with corticosteroids. Monitoring for development of Kaposi's sarcoma and alternative treatment may be beneficial for patients with IRIS, especially in the presence of preexisting co-infection with Kaposi's sarcoma-associated herpesvirus.