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BACKGROUND: A key to successful symptom management in patients with cancer is to adapt the treatment to patient needs and complexities in an individual and dynamic manner. Rapid access to a clinician via telephone consultation supports treatment compliance, safety, and effectiveness and reduces the number of patients unnecessarily consulting emergency departments. AIMS: To define the role of a cancer pain nurse in the management of unscheduled phone calls to the clinic. DESIGN: The study is a retrospective analysis of unscheduled phone calls received at an outpatient cancer pain clinic. Details collected included caller identification, reasons for the call, and interventions provided. Actions taken after analysis of the nature of calls are discussed. SETTINGS: Retrospective chart analysis. PARTICIPANTS/SUBJECTS: Medical charts of patients seen at the cancer pain clinic. METHODS: During three consecutive months, 102 unscheduled telephone calls fulfilling research criteria were analyzed. Seventy-four percent were initiated by patients or carers. In 46% and 45% of the calls, respectively, the reason for the call was to report a symptom or concern about the treatment. RESULTS: Pain was the most common reported symptom (59.6%) followed by side effects (23.4%). The most frequent inquiry about medications concerned renewal of prescriptions (47.8%). The most common intervention was related to patients' treatments (74.5%), and it included an element of teaching in 51.3% of calls. In one third of cases, a prescription was changed after the call. The nurse was able to provide the intervention without involving a doctor in 87.3% of calls. Several changes were initiated after the analysis to decrease unnecessary calls to the nurse. CONCLUSIONS: A telephone call service available for patients and other clinicians is an efficient way to enhance continuity of care for ambulatory patients. Continued efforts to make such a service cost effective must be implemented.
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Dor do Câncer/enfermagem , Enfermeiras e Enfermeiros/psicologia , Manejo da Dor/normas , Telefone , Adulto , Dor do Câncer/tratamento farmacológico , Dor do Câncer/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Estudos RetrospectivosRESUMO
BACKGROUND: TG6050 was designed as an improved oncolytic vector, combining the intrinsic properties of vaccinia virus to selectively replicate in tumors with the tumor-restricted expression of recombinant immune effectors to modify the tumor immune phenotype. These properties might be of particular interest for "cold" tumors, either poorly infiltrated or infiltrated with anergic T cells. METHODS: TG6050, an oncolytic vaccinia virus encodes single-chain human interleukin-12 (hIL-12) and full-length anti-cytotoxic T-lymphocyte-associated antigen-4 (@CTLA-4) monoclonal antibody. The relevant properties of TG6050 (replication, cytopathy, transgenes expression and functionality) were extensively characterized in vitro. The biodistribution and pharmacokinetics of the viral vector, @CTLA-4 and IL-12, as well as antitumoral activities (alone or combined with immune checkpoint inhibitors) were investigated in several "hot" (highly infiltrated) and "cold" (poorly infiltrated) syngeneic murine tumor models. The mechanism of action was deciphered by monitoring both systemic and intratumoral immune responses, and by tumor transcriptome analysis. The safety of TG6050 after repeated intravenous administrations was evaluated in cynomolgus monkeys, with a focus on the level of circulating IL-12. RESULTS: Multiplication and propagation of TG6050 in tumor cells in vitro and in vivo were associated with local expression of functional IL-12 and @CTLA-4. This dual mechanism translated into a strong antitumoral activity in both "cold" and "hot" tumor models (B16F10, LLC1 or EMT6, CT26, respectively) that was further amplified when combined with anti-programmed cell death protein-1. Analysis of changes in the tumor microenvironment (TME) after treatment with TG6050 showed increases in interferon-gamma, of CD8+T cells, and of M1/M2 macrophages ratio, as well as a drastic decrease of regulatory T cells. These local modifications were observed alongside bolstering a systemic and specific antitumor adaptive immune response. In toxicology studies, TG6050 did not display any observable adverse effects in cynomolgus monkeys. CONCLUSIONS: TG6050 effectively delivers functional IL-12 and @CTLA-4 into the tumor, resulting in strong antitumor activity. The shift towards an inflamed TME correlated with a boost in systemic antitumor T cells. The solid preclinical data and favorable benefit/risk ratio paved the way for the clinical evaluation of TG6050 in metastatic non-small cell lung cancer (NCT05788926 trial in progress).
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Antígeno CTLA-4 , Interleucina-12 , Vírus Oncolíticos , Microambiente Tumoral , Vaccinia virus , Animais , Vaccinia virus/genética , Camundongos , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Vírus Oncolíticos/imunologia , Feminino , Macaca fascicularis , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Terapia Viral Oncolítica/métodos , Neoplasias/terapia , Neoplasias/imunologiaRESUMO
Arming oncolytic viruses with transgenes encoding immunomodulators improves their therapeutic efficacy by enhancing and/or sustaining the innate and adaptive anti-tumoral immune responses. We report here the isolation, selection, and vectorization of a blocking anti-human PDL1 single-domain antibody (sdAb) isolated from PDL1-immunized alpacas. Several formats of this sdAb were vectorized into the vaccinia virus (VV) and evaluated for their programmed cell death protein 1 (PD1)/PD1 ligand (PDL1) blocking activity in the culture medium of tumor cells infected in vitro. In those conditions, VV-encoded homodimeric sdAb generated superior PDL1 blocking activity compared to a benchmark virus encoding full-length avelumab. The sdAb was further used to design simple, secreted, and small tumor necrosis factor superfamily (TNFSF) fusions with the ability to engage their cognate receptors (TNFRSF) only in the presence of PDL1-positive cells. Finally, PDL1-independent alternatives of TNFRSF agonists were also constructed by fusing different variants of surfactant protein-D (SP-D) oligomerization domains with TNFSF ectodomains. An optimal SP-D-CD40L fusion with an SP-D collagen domain reduced by 80% was identified by screening with a transfection/infection method where poxvirus transfer plasmids and vaccinia virus were successively introduced into the same cell. However, once vectorized in VV, this construct had a much lower CD40 agonist activity compared to the SP-D-CD40L construct, which is completely devoid of the collagen domain that was finally selected. This latest result highlights the importance of working with recombinant viruses early in the payload selection process. Altogether, these results bring several complementary solutions to arm oncolytic vectors with powerful immunomodulators to improve their immune-based anti-tumoral activity.
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BACKGROUND: Immune checkpoint blockade (ICB) is a clinically proven concept to treat cancer. Still, a majority of patients with cancer including those with poorly immune infiltrated 'cold' tumors are resistant to currently available ICB therapies. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of few clinically validated targets for ICB, but toxicities linked to efficacy in approved αCTLA-4 regimens have restricted their use and precluded full therapeutic dosing. At a mechanistic level, accumulating preclinical and clinical data indicate dual mechanisms for αCTLA-4; ICB and regulatory T cell (Treg) depletion are both thought to contribute efficacy and toxicity in available, systemic, αCTLA-4 regimens. Accordingly, strategies to deliver highly effective, yet safe αCTLA-4 therapies have been lacking. Here we assess and identify spatially restricted exposure to a novel strongly Treg-depleting, checkpoint-blocking, vectorized αCTLA-4, as a highly efficacious and potentially safe strategy to target CTLA-4. METHODS: A novel human IgG1 CTLA-4 antibody (4-E03) was identified using function-first screening for monoclonal antibodies (mAbs) and targets associated with superior Treg-depleting activity. A tumor-selective oncolytic vaccinia vector was then engineered to encode this novel, strongly Treg-depleting, checkpoint-blocking, αCTLA-4 antibody or a matching surrogate antibody, and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (VVGM-αCTLA-4). RESULTS: The identified 4-E03 antibody showed significantly stronger Treg depletion, but equipotent checkpoint blockade, compared with clinically validated αCTLA-4 ipilimumab against CTLA-4-expressing Treg cells in a humanized mouse model in vivo. Intratumoral administration of VVGM-αCTLA-4 achieved tumor-restricted CTLA-4 receptor saturation and Treg depletion, which elicited antigen cross-presentation and stronger systemic expansion of tumor-specific CD8+ T cells and antitumor immunity compared with systemic αCTLA-4 antibody therapy. Efficacy correlated with FcγR-mediated intratumoral Treg depletion. Remarkably, in a clinically relevant mouse model resistant to systemic ICB, intratumoral VVGM-αCTLA-4 synergized with αPD-1 to reject cold tumors. CONCLUSION: Our findings demonstrate in vivo proof of concept for spatial restriction of Treg depletion-optimized immune checkpoint blocking, vectorized αCTLA-4 as a highly effective and safe strategy to target CTLA-4. A clinical trial evaluating intratumoral VVGM-αhCTLA-4 (BT-001) alone and in combination with αPD-1 in metastatic or advanced solid tumors has commenced.
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Apresentação de Antígeno/imunologia , Antígeno CTLA-4/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , CamundongosRESUMO
To redress the immune imbalances created by pathologies such as cancer, it would be beneficial to create novel cytokine molecules, which combine desired cytokine activities with reduced toxicities. Due to their divergent but complementary activities, it is of interest to combine interleukin-2 (IL-2) and IL-18 into one recombinant molecule for immunotherapy. Evaluation of a fusokine protein that combines murine IL-2/IL-18 shows that it is stable, maintains IL-2 and IL-18 bioactivities, has notably reduced IL-2 associated toxicities, and has a novel lymphocyte-stimulating activity. An adeno-viral expression system was used to explore the biology of this "fusokine". Inclusion of the IL-18 prosequence (proIL-18) increases the expression, secretion, and potency of this fusokine. In vivo gene transfer experiments show that Ad-IL-2/proIL-18 dramatically outdoes Ad-IL-2, Ad-proIL-18, or the combination of both, by inducing high rates of tumor rejection in several murine models. Both innate and adaptive effector mechanisms are required for this antitumor activity.
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Imunoterapia Ativa/métodos , Interleucina-18/imunologia , Interleucina-2/imunologia , Proteínas Recombinantes de Fusão/imunologia , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Glicoproteínas/metabolismo , Humanos , Imunidade Inata/imunologia , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-18/biossíntese , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-2/biossíntese , Interleucina-2/genética , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2 , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina/metabolismo , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Linfócitos T/imunologiaRESUMO
Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146-57. ©2017 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon-alfa/antagonistas & inibidores , Neoplasias Experimentais/terapia , Terapia Viral Oncolítica/métodos , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vírus Oncolíticos , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Receptor de Interferon alfa e beta/metabolismo , Vaccinia virusRESUMO
OBJECTIVE: We report an exceptional case of non-islet cell tumor-induced hypoglycemia (NICTH) secondary to "Big"-IGF-2 oversecretion due to a giant phyllode tumor of the breast. CLINICAL PRESENTATION: A 49-year-old woman was admitted in emergency for brutal neurologic defect revealing severe hypoglycemia. Several similar episodes were observed throughout hospitalization, requiring continue perfusion of hypertonic glucose solution. Beside these metabolic disorders, we observed a giant and hard tumor of the left breast (about 30cm in diameter). INTERPRETATION: Supplementary blood analysis revealed serum levels of C-peptide and insulin suppressed during hypoglycemia, excluding the possibility of either endogenous or exogenous hyperinsulinism. Low plasma levels of GH and IGF-1 were found, suggesting a negative feedback loop on somatotroph axis function. Therefore, the hypothesis of an insulinomimetic compound released by tumor cells was evoked because of abnormal presence of high-weight and immature form of IGF-2 (called "Big"-IGF-2) in the serum identified by western immunoblot analysis. A left mastectomy was performed and completely restored glucose homeostasis and confirmed the paraneoplastic origin of hypoglycemia because of markedly elevated expression of IGF-2 mRNA (qPCR) within the tumor cells. Finally, the anatomopathology analysis diagnosed a mesenchymatous tumor, namely a high-grade phyllode sarcoma of the breast. CONCLUSION: Although NICTH due to "Big"-IGF-2 overproduction is a rare phenomenon, mainly observed in case of mesenchymatous tumor, it should be considered in presence of severe hypoglycemia with voluminous tumor and without hyperinsulinism.