Acute Kidney Injury Following Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma in a Kidney Transplant Recipient

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a newer and effective therapeutic option approved for patients with relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Acute kidney injury is a complication of CAR T-cell therapy that can result in kidney failure. In most cases, it is thought to be related to hemodynamic changes due to cytokine release syndrome. Kidney biopsy in this clinical scenario is usually not performed. We report on a kidney transplant recipient in his 40s who developed a posttransplant lymphoproliferative disorder of B-cell origin refractory to conventional treatments and received anti-CD19 CAR T-cell therapy as compassionate treatment. Beginning on day 12 after CAR T-cell infusion, in the absence of clinical symptoms, a progressive decline in estimated glomerular filtration rate of the kidney graft occurred. A subsequent allograft biopsy showed mild tubulointerstitial lymphocyte infiltrates, falling into a Banff borderline-changes category and resembling an acute immunoallergic tubulointerstitial nephritis. Neither CAR T cells nor lymphomatous B cells were detected within the graft cellular infiltrates, suggesting an indirect mechanism of kidney injury. Although kidney graft function partially recovered after steroid therapy, the posttransplant lymphoproliferative disorder progressed and the patient died 7 months later

Antigen glycosylation regulates efficacy of CAR T cells targeting CD19

While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy

Perspectives in immunotherapy: meeting report from the Immunotherapy Bridge (29-30 November, 2017, Naples, Italy)

Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno-oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these different immunotherapeutic options in various combinations with one another and with other treatment modalities is an area of particular promise. The third Immunotherapy Bridge meeting (29-30 November, 2017, Naples, Italy) focused on recent advances in immunotherapy across various cancer types and is summarised in this report

Brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone as frontline treatment for patients with CD30-positive B-cell lymphomas

We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850)

A lower intensity of treatment may underlie the increased risk of thrombosis in young patients with masked polycythaemia vera

In patients who do not meet the World Health Organization (WHO) criteria for overt polycythaemia vera (PV), a diagnosis of masked PV (mPV) can be determined. A fraction of mPV patients may display thrombocytosis, thus mimicking essential thrombocythaemia (ET). No previous studies have examined clinical outcomes of mPV among young JAK2-mutated patients. We analysed a retrospective cohort of 538 JAK2-mutated patients younger than 40 years, after a re-assessment of the diagnosis according to the haemoglobin threshold for mPV. In this cohort of patients, 97 (18%) met the WHO criteria for PV, 66 patients (12%) were classified as mPV and 375 (70%) as JAK2-mutated ET. Surprisingly, a significant difference in the incidence of thrombosis was found when comparing mPV versus overt PV patients (P = 0\ub704). In multivariate analysis, the only factor accounting for the difference in the risk of thrombosis was the less frequent use of phlebotomies and cytoreduction in mPV patients compared to those with overt PV. Thus, we emphasize the need for the identification of mPV in young JAK2-mutated patients in order to optimize their treatments

Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses

Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelinredirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-α and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA

Myeloablative doses of yttrium-90-ibritumomab tiuxetan and the risk of secondary myelodysplasia/acute myelogenous leukemia

Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium-90 (⁹⁰Y)-ibritumomab tiuxetan