The activity of recombinant human growth hormone (rhGH) in enhancing CD34+ cell mobilization elicited by chemotherapy plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) was ...evaluated in 16 hard-to-mobilize patients, that is, those achieving a peak of circulating CD34+ cells 10/μL or less, or a collection of CD34+ cells equal to or less than 2 × 106/kg. Patients who had failed a first mobilization attempt with chemotherapy plus rhG-CSF (5 μg/kg/d) were remobilized with chemotherapy plus rhG-CSF and rhGH (100 μg/kg/d). As compared with rhG-CSF, the combined rhGH/rhG-CSF treatment induced significantly higher (P ≤ .05) median peak values for CD34+ cells/μL (7 versus 29), colony-forming cells (CFCs)/mL (2154 versus 28 510), and long-term culture-initiating cells (LTC-ICs)/mL (25 versus 511). Following rhG-CSF and rhGH/rhG-CSF, the median yields of CD34+ cells per leukapheresis were 1.1 × 106/kg and 2.3 × 106/kg (P ≤ .008), respectively; the median total collections of CD34+ cells were 1.1 × 106/kg and 6 × 106/kg (P ≤ .008), respectively. No specific side effect could be ascribed to rhGH, except a transient hyperglycemia occurring in 2 patients. Reinfusion of rhGH/rhG-CSF-mobilized cells following myeloablative therapy resulted in prompt hematopoietic recovery. In conclusion, our data demonstrate that in poor mobilizers addition of rhGH to rhG-CSF allows the patients to efficiently mobilize and collect CD34+ cells with maintained functional properties. (Blood. 2004;103: 3287-3295)
Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not ...expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV+ lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV+ lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV+ lymphoid malignancies which are refractory to other regimens.
B cell malignancies express a clear tumor-specific antigen (B cell immunoglobulin variable regions) known as idiotype (Id). It is now possible to immunize patients against autologous Id generating ...humoral and cellular immune responses that correlate with clinical and molecular remissions and the possibility of improved disease-free survival. In its present form, however, individual vaccine preparation by generating heterohybridomas is a technical and financial challenge. DNA vaccination provides a unique opportunity to streamline individual vaccine manufacture by circumventing the need for protein purification. DNA fusion vaccines have been developed in which genetic carriers promote adaptive immunity against the attached Id. Such carriers can specifically bind receptors on dendritic cells (DC) for targeted antigen delivery, or supply high levels of T cell help. Ideally, the carrier should be able to activate innate immunity to enhance the antigen-presenting capacity of DC. The correlates of immunity may vary depending upon the genetic carrier used. Translation to patients has begun with preliminary evidence of Id-specific immune responses. An alternative vaccination strategy that allows for the potential to vaccinate against multiple tumor antigens without the need to identify individual antigens is based on tumor cells themselves to be used as vaccine. To this purpose, however, each patient's tumor cells must be genetically modified to increase their immunogenicity. To overcome the technical limitations inherent with a fully autologous approach, strategies have been devised where a universal, genetically modified bystander cells is expected to provide the immunoenhancing cytokines to allow immune recognition of unmodified patients' tumor cells.
Increasing evidence argues that the success of an anticancer treatment may rely on immunoadjuvant side effects including the induction of immunogenic tumor cell death. Based on the assumption that ...this death mechanism is a similar prerequisite for the efficacy of an active immunotherapy using killed tumor cells, we examined a vaccination strategy using dendritic cells (DC) loaded with apoptotic and necrotic cell bodies derived from autologous tumors. Using this approach, clinical and immunologic responses were achieved in 6 of 18 patients with relapsed indolent non-Hodgkin's lymphoma (NHL). The present report illustrates an impaired ability of the neoplastic cells used to vaccinate nonresponders to undergo immunogenic death on exposure to a cell death protocol based on heat shock, γ-ray, and UVC ray. Interestingly, when compared with doxorubicin, this treatment increased surface translocation of calreticulin and cellular release of high-mobility group box 1 and ATP in histologically distinct NHL cell lines. In contrast, treated lymphoma cells from responders displayed higher amounts of calreticulin and heat shock protein 90 (HSP90) compared with those from nonresponders and boosted the production of specific antibodies when loaded into DCs for vaccination. Accordingly, the extent of calreticulin and HSP90 surface expression in the DC antigenic cargo was significantly associated with the clinical and immunologic responses achieved. Our results indicate that a positive clinical effect is obtained when immunogenically killed autologous neoplastic cells are used for the generation of a DC-based vaccine. Therapeutic improvements may thus be accomplished by circumventing the tumor-impaired ability to undergo immunogenic death and prime the antitumor immune response.
•Epigenetics, and in particular, chromatin modifiers.•Cancer metabolism.•Cancer stem cells.•Tumor cell signaling.•The immune system.
During the Tenth Edition of the Annual Congress on “Anticancer ...Innovative Therapy” Milan, 23/24 January 2020, experts in the fields of immuno-oncology, epigenetics, tumor cell signaling, and cancer metabolism shared their latest knowledge on the roles of i epigenetics, and in particular, chromatin modifiers, ii cancer metabolism, iii cancer stem cells CSCs, iv tumor cell signaling, and iv the immune system. The novel therapeutic approaches presented included epigenetic drugs, cell cycle inhibitors combined with ICB, antibiotics and other off-label drugs, small-molecules active against CSCs, liposome-delivered miRNAs, tumor-specific CAR-T cells, and T-cell–based immunotherapy. Moreover, important evidence on possible mechanisms of resistance to these innovative therapies were also discussed, in particular with respect to resistance to ICB. Overall, this conference provided scientists and clinicians with a broad overview of future challenges and hopes to improve cancer treatment reasonably in the medium-short term.
Elimination of neoplastic cells from peripheral blood progenitor cells (PBPCs) is an important issue in transplantation-based high-dose chemotherapy in non Hodgkin's lymphoma (NHL). The capacity to ...reliably assess the presence of residual lymphoma cells in PBPCs is mandatory in designing this type of protocols. Polymerase chain reaction (PCR) amplification of molecular rearrangements is widely used to detect minimal residual disease (MRD) in NHL patients. Although concordant data can be obtained in most of the cases from peripheral blood (PB) and bone marrow (BM) at diagnosis, the relationship between these two compartments and the role of their analysis in predicting the molecular status of PBPCs is still an open issue. Here we report data about MRD analysis in BM, PB and PBPCs in a series of mantle cell and indolent NHL patients who underwent high-dose chemotherapy: discordant results were obtained comparing PB, BM and PBPC molecular data. In addition, differences were noted among these results if molecular analysis was performed using well-known rearrangements (i.e., bcl-1/IgH and bcl-2/IgH) or patient specific oligonucleotides. We conclude that neither BM nor PB are reliable in predicting the molecular status of PBPCs and that caution must be adopted in interpreting molecular data obtained using patient specific oligonucleotides.
Abstract Immunotherapy for the treatment of cancer has made significant progresses over the last 20 years. Multiple efforts have been attempted to restore immune-mediated tumor elimination, leading ...to the development of several targeted immunotherapies. Data from recent clinical trials suggest that these agents might improve the prognosis of patients with advanced genito-urinary (GU) malignancies. Nivolumab has been the first immune checkpoint-inhibitor approved for pre-treated patients with metastatic renal cell carcinoma. Pembrolizumab and atezolizumab have shown promising results in both phase I and II trials in urothelial carcinoma. Brentuximab vedotin has demonstrated early signals of clinical activity and immunomodulatory effects in highly pre-treated patients with testicular germ cell tumors. In this review, we have summarized the major clinical achievements of immunotherapy in GU cancers, focusing on immune checkpoint blockade as well as the new immunomodulatory monoclonal antibodies (mAbs) under clinical evaluation for these malignancies.
Summary
High‐dose chemotherapy (HDT) with autologous stem cell transplantation is the standard of care for relapsed/refractory (RR) Hodgkin lymphoma (HL). Given that HDT may cure a sizeable ...proportion of patients refractory to first salvage, development of newer conditioning regimens remains a priority. We present the results of a novel HDT regimen in which carmustine was substituted by a third‐generation chloroethylnitrosourea, fotemustine, with improved pharmacokinetics and safety (FEAM; fotemustine, etoposide, cytarabine, melphalan) in 122 patients with RR‐HL accrued into a prospective registry‐based study. Application of FEAM resulted in a 2‐year progression‐free survival (PFS) of 73·8% 95% confidence interval (CI), 0·64–0·81 with median PFS, overall survival and time to progression yet to be reached. The 2‐year risk of progression adjusted for the competitive risk of death was 19·4% (95% CI, 0·12–0·27) for the entire patient population. Most previously established independent risk factors, except for fluorodeoxyglucose (18FFDG)‐uptake, were unable to predict for disease progression and survival after FEAM. Although 32% of patients had 18FFDG‐positrin emission tomography‐positive lesions before HDT, the 2‐year risk of progression adjusted for competitive risk of death was 19·4% (95% CI; 0·12–0·27). No unusual acute toxicities or early/late pulmonary adverse events were registered. FEAM emerges as an ideal HDT regimen for RR‐HL patients typically pre‐exposed to lung‐damaging treatments.
Abstract The explosion in the immuno-oncology field, exemplified by the clinical implementation of immune checkpoint inhibitor blockade and other immunotherapeutic strategies was quickly recognized ...by the Italian biomedical community, thanks to the networking activities of the Italian Network for Tumor Biotherapy (NIBIT), which has been active since 2004 in the diffusion of new scientific and clinical findings in the fields of tumor immunology and immunotherapy. Numerous activities of NIBIT have also helped to overcome the hurdles associated with the clinical implementation of cancer immune-biotherapeutic strategies at the national and international levels. Looking forward, a concerted interaction of NIBIT with existing European networks focused on cancer bio-immunotherapy will further contribute to the development of improved therapies in the immuno-oncology field. This Introduction briefly summarizes the history and objectives of NIBIT, as well as the current activities of the Network.
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