Epstein-Barr Virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.

Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.

FOLFIRI in advanced platinum-resistant/refractory small-cell lung cancer: a retrospective study.

BACKGROUND: Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer and is associated with poor prognosis. In platinum-refractory or -resistant SCLC patients, few treatment options are available. Topotecan is one of the standards of care for these patients, however, due to its high toxicity, several different approaches are employed. FOLFIRI (folinate, 5-fluorouracil and irinotecan) is a chemotherapy regimen used in digestive neuroendocrine carcinoma, which shares pathological similarities with SCLC. In this retrospective study, we evaluated the efficacy and safety of FOLFIRI in patients with platinum-resistant/refractory SCLC. METHODS: Medical records from all consecutive SCLC patients treated with FOLFIRI in a French University Hospital from 2013 to 2021 were analyzed retrospectively. The primary endpoint was the objective response rate according to RECIST v1.1 or EORTC criteria (ORR); secondary endpoints included duration of response, disease control rate, progression-free survival (PFS), overall survival (OS) and safety profile. RESULTS: Thirty-four patients with metastatic platinum-resistant (n = 14) or -refractory (n = 20) SCLC were included. Twenty-eight were evaluable for response, with a partial response observed in 5 patients for an overall ORR in the evaluable population of 17.9% (5/28) and 14.7% (5/34) in the overall population. The disease control rate was 50% (14/28) in the evaluable population. The median PFS and OS were 2.8 months (95%CI, 2.0-5.2 months) and 5.3 months (95%CI, 3.5-8.9 months), respectively. All patients were included in the safety analysis. Grade 3 or 4 adverse events occurred in 13 (38.2%) patients. The most common grade 3 or 4 adverse events were asthenia, neutropenia, thrombopenia and diarrhea. There was no adverse event leading to discontinuation or death. CONCLUSION: FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response and had an acceptable safety profile. However, caution is needed in interpreting this result. FOLFIRI could represent a potential new treatment for platinum-resistant/refractory SCLC patients. Further prospective studies are needed to assess the benefits of this chemotherapy regimen.HIGHLIGHTSFOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response.FOLFIRI was well-tolerated in platinum resistant/refractory SLCL patients.FOLFIRI could represent a potential new treatment for SCLC, prospective studies are needed.

Recurrence and Occurrence of Kaposi's Sarcoma in Patients Living With Human Immunodeficiency Virus (HIV) and on Antiretroviral Therapy, Despite Suppressed HIV Viremia.

In 21 cutaneous and/or visceral Kaposi's sarcoma cases, occurring in patients living with human immunodeficiency virus (HIV) who were on antiretroviral therapy with suppressed HIV viremia and high CD4 T cell counts, the efficacy of conventional chemotherapies was limited due to cumulative toxicities, comedications, and a lack of immune improvement.

Immune Reconstitution Inflammatory Syndrome Associated Kaposi Sarcoma.

People living with HIV (PLWH) with advanced immunosuppression who initiate antiretroviral therapy (ART) are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Although ART is responsible for AIDS- associated Kaposi sarcoma (KS) improvement and resolution, new onset (unmasking KS-IRIS) or sudden progression of preexisting KS (paradoxical KS-IRIS) can occur after a time delay of between a few days and 6 months after the initiation or resumption of ART, even in patients with a low degree of immunocompromise. KS-IRIS incidence varies from 2.4% to 39%, depending on study design, populations, and geographic regions. Risk factors for developing KS-IRIS include advanced KS tumor stage (T1), pre-treatment HIV viral load >5 log10 copies/mL, detectable pre-treatment plasma-KSHV, and initiation of ART alone without concurrent chemotherapy. Both paradoxical and unmasking KS-IRIS have been associated with significant morbidity and mortality, and thrombocytopenia (<100,000 platelets/mm3 at 12 weeks) has been associated with death. KS-IRIS is not to be considered as ART failure, and an ART regimen must be pursued. Systemic chemotherapy for KS in conjunction with ART is recommended and, in contrast with management of IRIS for other opportunistic infections, glucocorticoids are contra-indicated. Despite our preliminary results, the place of targeted therapies in the prevention or treatment of KS-IRIS needs further assessment.

Therapeutic Perspectives in the Systemic Treatment of Kaposi's Sarcoma.

In patients with Kaposi's sarcoma (KS), the therapeutic goal is to achieve a durable remission in the size and number of skin and visceral lesions. Although most patients show tumor regression in response to standard systemic chemotherapy regimens, alternative systemic treatments are needed for patients who develop refractory KS. Anti-angiogenic therapies represent attractive therapeutic targets in this context, due to the central role of angiogenesis in KS pathogenesis. Pomalidomide, which exhibits such anti-angiogenic activity through inhibition of VEGF, currently constitutes the most promising agent of this class and has been recently approved by the FDA. In addition, immune checkpoint blockade also represents an interesting alternative therapeutic approach through the restoration of immunity against HHV-8, the causative agent of KS, and improvement of tumor control. Although small series of cases treated successfully with these drugs have been reported, there is no marketing approval for anti-immune checkpoint antibodies for KS to date. In the present review, we will discuss potential therapeutic options for patients with recurrent or refractory KS, including systemic chemotherapies, immune checkpoint inhibitors, anti-herpesvirus agents, and anti-angiogenic drugs. Well-conducted clinical trials in this population are urgently needed to correctly address the efficacy of targeted agents and immunomodulators, while monitoring for adverse effects.

Impact of Anti PD-1 Immunotherapy on HIV Reservoir and Anti-Viral Immune Responses in People Living with HIV and Cancer.

The role of immune checkpoints (ICPs) in both anti-HIV T cell exhaustion and HIV reservoir persistence, has suggested that an HIV cure therapeutic strategy could involve ICP blockade. We studied the impact of anti-PD-1 therapy on HIV reservoirs and anti-viral immune responses in people living with HIV and treated for cancer. At several timepoints, we monitored CD4 cell counts, plasma HIV-RNA, cell associated (CA) HIV-DNA, EBV, CMV, HBV, HCV, and HHV-8 viral loads, activation markers, ICP expression and virus-specific T cells. Thirty-two patients were included, with median follow-up of 5 months. The CA HIV-DNA tended to decrease before cycle 2 (p = 0.049). Six patients exhibited a ≥0.5 log10 HIV-DNA decrease at least once. Among those, HIV-DNA became undetectable for 10 months in one patient. Overall, no significant increase in HIV-specific immunity was observed. In contrast, we detected an early increase in CTLA-4 + CD4+ T cells in all patients (p = 0.004) and a greater increase in CTLA-4+ and TIM-3 + CD8+ T cells in patients without HIV-DNA reduction compared to the others (p ≤ 0.03). Our results suggest that ICP replacement compensatory mechanisms might limit the impact of anti-PD-1 monotherapy on HIV reservoirs, and pave the way for combination ICP blockade in HIV cure strategies.

Brief Report of Anti-Programmed Cell Death Protein-1 in Human Immunodeficiency Virus Setting: Relevant and Breaking Results in First-Line NSCLC Therapy.

In the recent past, we observed an increased risk of cancer in the population with human immunodeficiency virus (HIV) owing to the development of antiretroviral therapies that decreased mortality caused by HIV-specific infections. This particularly fragile population is frequently excluded from clinical trials, and up-to-date recommendations for these patients are lacking. Only few cases of patients with HIV suffering from cancer and undergoing first-line immunotherapy have been reported so far. Here, we report the largest known study of patients with HIV with NSCLC (five patients) undergoing first-line immunotherapy by pembrolizumab, after CANCERVIH group selection. Our results are consistent with those of previous case reports concerning safety of immunotherapy in patients with HIV, revealing no severe or fatal toxicity, opportunistic infections, or immune reconstitution inflammatory syndrome. Moreover, pembrolizumab did not seem to modify HIV viral parameters. We also evaluated the effectiveness of immunotherapy in these HIV-immunosuppressed patients: the average survival was 9.8 months, with three patients having rapid progression and two partial response. Nevertheless, besides safety and drug-to-drug interactions, the effectiveness of first-line immunotherapy in people living with HIV needs to be supported by larger studies.

Kaposi's Sarcoma-Associated Herpesvirus, the Etiological Agent of All Epidemiological Forms of Kaposi's Sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is an oncogenic virus belonging to the Herpesviridae family. The viral particle is composed of a double-stranded DNA harboring 90 open reading frames, incorporated in an icosahedral capsid and enveloped. The viral cycle is divided in the following two states: a short lytic phase, and a latency phase that leads to a persistent infection in target cells and the expression of a small number of genes, including LANA-1, v-FLIP and v-cyclin. The seroprevalence and risk factors of infection differ around the world, and saliva seems to play a major role in viral transmission. KSHV is found in all epidemiological forms of Kaposi's sarcoma including classic, endemic, iatrogenic, epidemic and non-epidemic forms. In a Kaposi's sarcoma lesion, KSHV is mainly in a latent state; however, a small proportion of viral particles (<5%) are in a replicative state and are reported to be potentially involved in the proliferation of neighboring cells, suggesting they have crucial roles in the process of tumorigenesis. KSHV encodes oncogenic proteins (LANA-1, v-FLIP, v-cyclin, v-GPCR, v-IL6, v-CCL, v-MIP, v-IRF, etc.) that can modulate cellular pathways in order to induce the characteristics found in all cancer, including the inhibition of apoptosis, cells' proliferation stimulation, angiogenesis, inflammation and immune escape, and, therefore, are involved in the development of Kaposi's sarcoma.

Do people living with HIV face more secondary cancers than general population: From the French CANCERVIH network.

INTRODUCTION: People living with HIV (PLWHIV) are at a higher risk of cancer compared to the general population. With improved cancer treatments and the increased life expectancy of PLWHIV, the incidence of second cancers is also expected to increase. METHODS: We reviewed the cases of PLWHIV with cancer that have been presented to the CANCERVIH national multidisciplinary board since 2014. We included all cases with a history of cancer, and studied the incidence and types of second cancers. RESULTS: In total, 719 cases were reviewed, out of which 94 (13%) had a history of at least one cancer. For the first primary cancers, 46 (49%) were AIDS-defining cancers (ADCs) and 48 (51%) were non-AIDS-defining cancers (NADCs). Kaposi sarcoma (33%) and NHL (15%) occurred most frequently as first cancers. Among the first cancers that were ADCs, 15% of the second cancers were NHL, 11% anal canal cancers, 9% bladder and 9% Hodgkin lymphomas. Among the first cancers that were NADCs, 38% of the second cancers were lung cancers, 8% bladder, 8% head and neck and 8% NHL. DISCUSSION: With the aging of PLWHIV, the incidence of second and subsequent cancers is expected to increase in this population. Immuno-virological control should be maintained. Increased surveillance, early prevention and screening programs should be offered to all PLWHIV, including those with an undetectable HIV viral load and/or immune restoration.

Kaposi's Sarcoma in Virally Suppressed People Living with HIV: An Emerging Condition.

Since the advent of highly effective combined antiretroviral treatment (cART), and with the implementation of large HIV testing programs and universal access to cART, the burden of AIDS-related comorbidities has dramatically decreased over time. The incidence of Kaposi's sarcoma (SK), strongly associated with HIV replication and CD4 immunosuppression, was greatly reduced. However, KS remains the most common cancer in patients living with HIV (PLHIV). HIV physicians are increasingly faced with KS in virally suppressed HIV-patients, as reflected by increasing description of case series. Though SK seem less aggressive than those in PLHIV with uncontrolled HIV-disease, some may require systemic chemotherapy. Persistent lack of specific anti-HHV-8 cellular immunity could be involved in the physiopathology of these KS. These clinical forms are a real therapeutic challenge without possible short-term improvement of anti-HHV-8 immunity, and no active replication of HIV to control. The cumulative toxicity of chemotherapies repeatedly leads to a therapeutic dead end. The introduction or maintenance of protease inhibitors in cART does not seem to have an impact on the evolution of these KS. Research programs in this emerging condition are important to consider new strategies.

[Survey on HIV, HBV and HCV screening practices in cancerology, France]. / Enquête sur la pratique du dépistage du VIH, VHB et VHC en cancérologie, France.

HIV testing is recommended at time of cancer diagnosis, HBV and HCV screening because of the risk of reactivation with certain anticancer drugs.This is a cross-sectional study. The objectives were to assess the screening practices in cancer patients and the satisfaction of professionals in the event of use of the CancerHIV network. A questionnaire drafted by the CancerHIV expert and the OncoPaca-Corse Regional Cancer Network (RCN) was distributed in the region at the end of 2018 (part 1: V1) before being extended to the national level via the CancerHIV network (part 2: V2). Participation reached 160 and 130 respondents (V1 and V2, respectively). At the initial cancer assessment, 23% of respondents declared that they systematically screened for HIV at V1 (V2: 17%), 25% for HBV (V2: 20%) and 24% for HCV (V2: 19%). Before immunotherapy, the rates were 54% for HIV in V1 (V2: 52%), 57% for HBV (V2: 60%) and 55% for HCV (V2: 57%). Among the respondents, satisfaction when requesting a regional or national remedy was high (almost 100%). Screening for HIV, HBV and HCV allows supervised prescription of immunosuppressive or cytotoxic treatment to a potentially immunosuppressed patient. This study, resulting of an original collaboration between a RCN and a national expert network, underlines the lack of screening at the 2 examined stages of patient care, and the need for raising practitioners' awareness to recommendations.

Low-Coverage Whole Genome Sequencing of Cell-Free DNA From Immunosuppressed Cancer Patients Enables Tumor Fraction Determination and Reveals Relevant Copy Number Alterations.

Cell-free DNA (cfDNA) analysis is a minimally invasive method that can be used to detect genomic abnormalities by directly testing a blood sample. This method is particularly useful for immunosuppressed patients, who are at high risk of complications from tissue biopsy. The cfDNA tumor fraction (TF) varies greatly across cancer type and between patients. Thus, the detection of molecular alterations is highly dependent on the circulating TF. In our study, we aimed to calculate the TF and characterize the copy number aberration (CNA) profile of cfDNA from patients with rare malignancies occurring in immunosuppressed environments or immune-privileged sites. To accomplish this, we recruited 36 patients: 19 patients with non-Hodgkin lymphoma (NHL) who were either human immunodeficiency virus (HIV)-positive or organ transplant recipients, 5 HIV-positive lung cancer patients, and 12 patients with glioma. cfDNA was extracted from the patients' plasma and sequenced using low-coverage whole genome sequencing (LC-WGS). The cfDNA TF was then calculated using the ichorCNA bioinformatic algorithm, based on the CNA profile. In parallel, we performed whole exome sequencing of patient tumor tissue and cfDNA samples with detectable TFs. We detected a cfDNA TF in 29% of immune-suppressed patients (one patient with lung cancer and six with systemic NHL), with a TF range from 8 to 70%. In these patients, the events detected in the CNA profile of cfDNA are well-known events associated with NHL and lung cancer. Moreover, cfDNA CNA profile correlated with the CNA profile of matched tumor tissue. No tumor-derived cfDNA was detected in the glioma patients. Our study shows that tumor genetic content is detectable in cfDNA from immunosuppressed patients with advanced NHL or lung cancer. LC-WGS is a time- and cost-effective method that can help select an appropriate strategy for performing extensive molecular analysis of cfDNA. This technique also enables characterization of CNAs in cfDNA when sufficient tumor content is available. Hence, this approach can be used to collect useful molecular information that is relevant to patient care.

[HIV and cancer: Update 2020]. / VIH et cancer : mise au point en 2020.

The HIV infection remains a serious public health concern in France and around the world. Cancers are frequent among people living with HIV (PLWH) and have become the leading cause of mortality among this population in France. Certain non-AIDS-defining cancers are much more common among PLWH, such as anal carcinoma, Hodgkin lymphoma, hepatocellular carcinoma and lung cancer. The incidence of cancer among PLWH depending on various factors, virological control under combined antiretrovial therapies (cART), exposure prevention to oncogenic virus and toxics are of utmost importance, such as the implementation of specific screening programmes. Drug interactions between cART and oncologic treatments can lead to serious adverse effects or to a reduction in the therapeutic effects, therefore they require a close monitoring. The PLWH have been excluded from the oncologic clinical trials assessing the efficacy and toxicity profile of the immune checkpoints inhibitors (ICPi) because of an increased theoretical risk of inducing adverse events and a feared lack of efficacy in the immunocompromised population. However, the mostly retrospective clinical data reporting the use of ICPi among PLWH are somewhat reassuring with a safety and efficacy profile similar to what observed in HIV-negative patients. Regarding the "shock and kill" anti-HIV effects of ICPi, the preliminary clinical data available are still modest and relatively disappointing despite encouraging results obtained in vitro. HIV-associated cancers represent a particular care challenge due to the multiple comorbidities in the population and the high risk of drug interactions, thus the CANCERVIH national network is of particular interest within this context.

Immune checkpoint inhibitors in people living with HIV: what about anti-HIV effects?

: Immune checkpoint inhibitors (ICPi) have shown major therapeutic successes when used in various cancers. In the HIV field a double benefit of such ICPi should result from their dual ability to restore in-vitro HIV-specific CD8 T-cell functions and to enhance HIV production from reservoir cells, thus fulfilling the goals of the 'shock and kill' concept proposed as an HIV cure therapeutic strategy. We conducted a systematic review to identify studies reporting the tolerance profile of ICPi and their effects on HIV plasma loads (pVL), CD4 cell count, HIV reservoirs (cell-associated HIV-DNA) and/or HIV-specific CD8 T cells in PLWH. Thirty-one articles were included for a total 176 participants. Twelve percent of the participants experienced severe adverse events and 49% nonsevere adverse events. pVL remained stable in 91.9% participant, showed increases in 5.8% participant, and decreases in 2.3%. CD4 cell count remained stable in 60.7% participants, showed increases in 24.6%, and decreases in 14.7%. Regarding ICPi effects on HIV-DNA and HIV-specific immunity, we identified three distinct profiles: profile I, transient pVL increases followed by a boost in HIV-specific CD8 T cells concomitant to a decrease in HIV-DNA, reported in one participant. Profile II: increase in HIV-specific CD8 T cells without changes in pVL or HIV-DNA, reported in three participants. III: no effect, reported in five participants. In conclusion, the clinical, virological and immunological safety profiles of ICPi reported in about 200 PLWH appear to be favorable but there are still modest results in terms of HIV cure strategy.

Immunotherapy for cancer in people living with HIV: safety with an efficacy signal from the series in real life experience.

OBJECTIVE: To report efficacy and tolerance of nivolumab or pembrolizumab, PD-1 inhibitors, in people living with HIV (PLWHIV) and cancer. DESIGN: Series of PLWHIV cancer patients treated with anti-PD1 agents in real-life clinical practice. METHODS: From May 2014 to January 2019, 575 HIV-infected patients have been discussed in the French CANCERVIH national multidisciplinary board and included in the network database. Twenty-three patients were treated with immune checkpoint inhibitors in daily practice. We report the demographic characteristics, CD4 T-cell counts, HIV viral loads, safety and efficacy data of these 23 PLWHIV treated in routine practice with nivolumab or pembrolizumab for nonsmall cell lung cancer (n = 21), melanoma (n = 1) and head and neck cancer (n = 1) retrospectively collected from the database CANCERVIH network. The median CD4 T-cell count at treatment initiation was 370 cells/µl (IQR: 125-1485). HIV viral load was undetectable in all patients. RESULTS: As of 29 April 2019, with a median follow-up of 10.8 months (2.0-27.7), the median number of injections was 6 (IQR: 4-18). Only two grade 3 adverse reactions were reported (no toxic deaths or immune-related deaths). Among the 23 patients, a partial response was observed in five patients (22%), a stabilization for five (22%) and a progression in 13 (57%). Only one patient experienced a positive HIV viral load, but this occurred following ART interruption. CONCLUSION: Treatment with PD-1 inhibitors seems to have an efficacy signal and be well tolerated in PLWHIV, including impact on CD4 lymphocyte count and HIV load, that should be monitored during treatment course (regarding real-life experience).

[HIV and cancer : What's new in 2017?] / Cancer et VIH : actualités 2017.

Since the era of combined antiretroviral therapy, life expectancy of people living with HIV has been improved and is associated with a change in causes of death. Cancer, both AIDS-defining or non-AIDS-defining cancers, has become the leading cause of death in people living with HIV associated with an increase in the incidence of some cancers compared to the general population. Epidemiology and the identification of risk factors is a crucial issue, particularly to determine the most appropriate prevention and screening strategies in this population. In the absence of dedicated clinical trials, the cancer management in these patients is based on general recommendations, with specific attention to comorbidities and drug interactions. In addition, the development of new innovative therapies such as immunotherapy with inhibitory antibodies of immune checkpoints receptor represents a hope for the patient care, both infected or not with HIV. In this context, the establishment of the national network CancerVIH makes sense, allowing the establishment of multi-disciplinary consultation meetings involving all the practitioners involved in the care of these patients with cancer, as well as the constitution of a national cohort and the promotion of dedicated trials, to improve and optimize the management for these patients.