• Check(point) or checkmate for acute myeloid leukemia?

      Niyongere, Sandrine; Rapoport, Aaron P (Ferrata Storti Foundation, 2021-05-01)
    • Deep dissection of the antiviral immune profile of patients with COVID-19.

      Atanackovic, Djordje; Avila, Stephanie V; Lutfi, Forat; de Miguel-Perez, Diego; Fan, Xiaoxuan; Sanchez-Petitto, Gabriela; Vander Mause, Erica; Siglin, Jonathan; Baddley, John; Mannuel, Heather D; et al. (Springer Nature, 2021-12-16)
      In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 "South African" variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-β) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.
    • Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine.

      Saharia, Kapil K; Husson, Jennifer S; Niederhaus, Silke V; Iraguha, Thierry; Avila, Stephanie V; Yoo, Youngchae J; Hardy, Nancy M; Fan, Xiaoxuan; Omili, Destiny; Crane, Alice; et al. (Wiley-Blackwell, 2022-04-29)
      Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titres against SARS-CoV-2 and its delta variants and fewer linear B-cell epitopes, indicating reduced B-cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti-SARS-CoV-2 CD4+ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS-CoV-2 and the improvement in neutralising activity was much less pronounced than for all the other variants.
    • Low-affinity CAR T cells exhibit reduced trogocytosis, preventing rapid antigen loss, and increasing CAR T cell expansion.

      Olson, Michael L; Mause, Erica R Vander; Radhakrishnan, Sabarinath V; Brody, Joshua D; Rapoport, Aaron P; Welm, Alana L; Atanackovic, Djordje; Luetkens, Tim (Springer Nature, 2022-04-30)
    • Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas

      Major, Ajay; Kline, Justin; Karrison, Theodore G; Fishkin, Paul A S; Kimball, Amy S; Petrich, Adam M; Nattam, Sreenivasa; Rao, Krishna; Sleckman, Bethany G; Cohen, Kenneth; et al. (Ferrata Storti Foundation, 2021-07-29)
      The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of 4 (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of 6 prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic AEs were common. Three grade 5 AEs occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL. ClinicalTrials.gov identifier: NCT01076543.
    • Prolonged Lenalidomide Induction Does Not Significantly Impair Stem Cell Collection in Multiple Myeloma Patients Mobilized With Cyclophosphamide or Plerixafor: A Report From The Covid Era.

      Rybinski, Brad; Rapoport, Aaron P; Badros, Ashraf Z; Hardy, Nancy; Kocoglu, Mehmet (Elsevier, 2022-03-28)
      Patients who received prolonged induction were more likely to require >1 day of apheresis (38% vs. 15%; OR 3.45; P = .0154), and there was a significant correlation between the duration of lenalidomide treatment and the apheresis time required to collect sufficient cells for transplant (R2 = 0.06423, P = .0148). However, there was no significant difference between patients who received prolonged induction and those who did not with respect to CD34+ stem cell yields at completion of apheresis (9.99 vs. 10.46 cells/Kg, P = .5513) or on the first day of collection (8.29 vs. 9.59 cells/Kg, P = .1788).
    • The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

      Shah, Nina; Aiello, Jack; Avigan, David E; Berdeja, Jesus G; Borrello, Ivan M; Chari, Ajai; Cohen, Adam D; Ganapathi, Karthik; Gray, Lissa; Green, Damian; et al. (BMJ, 2020-07-12)
      Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.
    • Successful transfer of anti-SARS-CoV-2 immunity using convalescent plasma in an MM patient with hypogammaglobulinemia and COVID-19

      Luetkens, Tim; Metcalf, Ryan; Planelles, Vicente; Zheng, Yue; Larragoite, Erin T; Spivak, Emily S; Spivak, Adam M; Steinbach, Mary; Blaylock, Robert C; Avila, Stephanie V; et al. (American Society of Hematology, 2020-10-08)