Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment.

BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.

Medical costs of treatment and survival of patients with acute myeloid leukemia in Belgium.

The advent of new cell-based immunotherapies for leukemia offers treatment possibilities for certain leukemia subgroups. The wider acceptability of these new technologies in clinical practice will depend on its impact on survival and costs. Due to the small patient groups who have received it, these aspects have remained understudied. This non-randomized single-center study evaluated medical costs and survival for acute myeloid leukemia between 2005 and 2010 in 50 patients: patients treated with induction and consolidation chemotherapy (ICT) alone; patients treated with ICT plus allogeneic hematopoietic stem cell transplantation (HCT), which is the current preferred post-remission therapy in patients with intermediate- and poor-risk AML with few co-morbidities, and patients treated with ICT plus immunotherapy using autologous dendritic cells (DC) engineered to express the Wilms' tumor protein (WT1). Total costs including post- consolidation costs on medical care at the hematology ward and outpatient clinic, pharmaceutical prescriptions, intensive care ward, laboratory tests and medical imaging were analyzed. Survival was markedly better in HCT and DC. HCT and DC were more costly than ICT. The median total costs for HCT and DC were similar. These results need to be confirmed to enable more thorough cost-effectiveness analyses, based on observations from multicenter, randomized clinical trials and preferably using quality-adjusted life-years as an outcome measure.

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia.

The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

Immunotherapy in leukaemia.

Therapeutic cancer vaccination, e.g. by using tumour antigen-presenting dendritic cells (DCs) that 'educate' the immune system to recognise and attack tumour cells, represents a new concept of treatment in oncology. DCbased immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DCs emerge as a feasible and effective strategy to control residual disease in acute myeloid leukaemia (AML), in particular as a post-remission treatment to prevent full relapse. This innovative approach takes advantage of the intrinsic potential of the immune system to eradicate malignant disease.

Interferon-α in acute myeloid leukemia: an old drug revisited.

Interferon-α (IFN-α), a type I IFN, is a well-known antitumoral agent. The investigation of its clinical properties in acute myeloid leukemia (AML) has been prompted by its pleiotropic antiproliferative and immune effects. So far, integration of IFN-α in the therapeutic arsenal against AML has been modest in view of the divergent results of clinical trials. Recent insights into the key pharmacokinetic determinants of the clinical efficacy of IFN along with advances in its pharmaceutical formulation, have sparked renewed interest in its use. This paper reviews the possible applicability of IFN-α in the treatment of AML and provides a rational basis to re-explore its efficacy in clinical trials.

Long-term outcomes after ROLL lumpectomy.

BACKGROUND: Occult breast lesions are being successfully targeted by means of Radioactive-guided Occult Lesion Localization (ROLL). Several reports demonstrate suitability of ROLL technique to excise non-palpable breast lesions with immediate advantages. AIM: Evaluation of long-term outcomes after ROLL guided lumpectomy for early breast cancer. MATERIALS AND METHODS A CONSECUTIVE SERIES OF NON PALPABLE EARLY INVASIVE BREAST CANCERS EXCISED WITH ROLL (151 PTS; DECEMBER 2002#ENTITYSTARTX02013;JUNE 2006) WERE FOLLOWED UP FOR LONG-TERM OUTCOMES, I.E. LOCAL AND/OR SYSTEMIC RECURRENCE. OUR FOLLOW-UP PROTOCOL INCLUDED 6 MONTHLY PHYSICIAN ADMINISTERED CLINICAL EXAMINATIONS AND 18 MONTHLY IMAGING, I.E. MAMMOGRAM. BONE SCAN, LIVER AND BRAIN IMAGING WERE REQUESTED ON CLINICAL NEED. CLINICAL AND/OR RADIOLOGICAL SUSPICIOUS LESIONS FOR LOCAL RECURRENCE WERE CONFIRMED PATHOLOGICALLY: RESULTS: The median follow-up was 46 months with all patients having a minimum 22 months follow-up. 3/151 local recurrences occurred (1.98%). CONCLUSIONS: Long-term outcomes, i.e. local recurrence of invasive breast cancer excised with ROLL guidance compares well with existing localization techniques.

Recurrence after ROLL lumpectomy for invasive breast cancer.

BACKGROUND: Impalpable breast lesions are being successfully targeted by means of radio-guided occult lesion localisation (ROLL). Although ROLL allows adequate removal of sub-clinical breast lesions within a smaller volume of glandular tissue no long-term outcomes have been reported. AIM: To evaluate the recurrence of invasive cancer after ROLL lumpectomy. METHODS: A consecutive series of impalpable invasive breast cancers excised with ROLL (151 pts; Dec 2002-June 2006) has been followed up for local and/or systemic recurrence with six monthly clinical examinations and 18 monthly mammograms. Bone scan, liver and brain imaging were requested when clinically appropriate. Clinical and/or radiological suspicious lesions for local recurrence were confirmed pathologically. RESULTS: The median follow-up was 33 months with all patients having a minimum 22 months follow-up. Three (out of 151 impalpable invasive cancers) local recurrences occurred (1.98%). CONCLUSIONS: Local recurrence of sub-clinical invasive breast cancer excised with radioisotope guidance compares well with the existing localisation techniques. Its implementation is highly recommended.

Functional study on TRPV1-mediated signalling in the mouse small intestine: involvement of tachykinin receptors.

Afferent nerves in the gut not only signal to the central nervous system but also provide a local efferent-like effect. This effect can modulate intestinal motility and secretion and is postulated to involve the transient receptor potential of the vanilloid type 1 (TRPV1). By using selective TRPV1 agonist and antagonists, we studied the efferent-like effect of afferent nerves in the isolated mouse jejunum. Mouse jejunal muscle strips were mounted in organ baths for isometric tension recordings. Jejunal strips contracted to the TRPV1 agonist capsaicin. Contractions to capsaicin showed rapid tachyphylaxis and were insensitive to tetrodotoxin, hexamethonium, atropine or L-nitroarginine. Capsaicin did not affect contractions to electrical stimulation of enteric motor nerves and carbachol. Tachykinin NK1, NK2 and NK3 receptor blockade by RP67580, nepadutant plus SR-142801 reduced contractions to capsaicin to a similar degree as contractions to substance P. The effect of the TRPV1 antagonists capsazepine, SB-366791, iodo-resiniferatoxin (iodo-RTX) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) was studied. Capsazepine inhibited contractions not only to capsaicin but also those to carbachol. SB-366791 reduced contractions both to capsaicin and carbachol. Iodo-RTX partially inhibited the contractions to capsaicin without affecting contractions to carbachol. BCTC concentration-dependently inhibited and at the highest concentration used, abolished the contractions to capsaicin without affecting those to carbachol. From these results, we conclude that activation of TRPV1 in the mouse intestine induces a contraction that is mediated by tachykinins most likely released from afferent nerves. The TRPV1-mediated contraction does not involve activation of intrinsic enteric motor nerves. Of the TRPV1 antagonists tested, BCTC combined strong TRPV1 antagonism with TRPV1 selectivity.