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Introduction: Dabrafenib and trametinib are currently administered at fixed doses, at which interpatient variability in exposure is high. The aim of this study was to investigate whether drug exposure is related to efficacy and toxicity in a real-life cohort of melanoma patients treated with dabrafenib plus trametinib. Patients and methods: An observational study was performed in which pharmacokinetic samples were collected as routine care. Using estimated dabrafenib Area Under the concentration–time Curve and trametinib trough concentrations (Cmin), univariable and multivariable exposure–response analyses were performed. Results: In total, 140 patients were included. Dabrafenib exposure was not related to either progression-free survival (PFS) or overall survival (OS). Trametinib exposure was related to survival, with Cmin ≥ 15.6 ng/mL being identified as the optimal threshold. Median OS was significantly longer in patients with trametinib Cmin ≥ 15.6 ng/mL (22.8 vs. 12.6 months, P = 0.003), with a multivariable hazard ratio of 0.55 (95% CI 0.36–0.85, P = 0.007). Median PFS in patients with trametinib Cmin levels ≥ 15.6 ng/mL (37%) was 10.9 months, compared with 6.0 months for those with Cmin below this threshold (P = 0.06). Multivariable analysis resulted in a hazard ratio of 0.70 (95% CI 0.47–1.05, P = 0.082). Exposure to dabrafenib and trametinib was not related to clinically relevant toxicities. Conclusions: Overall survival of metastasized melanoma patients with trametinib Cmin levels ≥ 15.6 ng/mL is ten months longer compared to patients with Cmin below this threshold. This would theoretically provide a rationale for therapeutic drug monitoring of trametinib. Although a high proportion of patients are underexposed, there is very little scope for dose increments due to the risk of serious toxicity. [ABSTRACT FROM AUTHOR]

Background: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. Methods: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (≥ 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (≥ 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade ≥ 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. Discussion: Transplanting fecal microbiota to restore the patients’ perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. Trial registration: ClinicalTrials.gov: NCT05251389 (registered 22-Feb-2022). Protocol V4.0 (08–02-2022). [ABSTRACT FROM AUTHOR]

Cancer cells can escape the immune system by different mechanisms. The evasion of cancer cells from immune surveillance is prevented by immune checkpoint inhibitors, allowing the patient's own immune system to attack their cancer. Immune checkpoint inhibitors have shown improvement in overall survival for melanoma, lung cancer and renal cell carcinoma in clinical trials. Unfortunately, not all patients respond to this therapy. In cancer management, percutaneous ablation techniques are well established for both cure and local control of many tumour types. Cryoablation of the tumour tissue results in cell destruction by freezing. Contrary to heat-based ablative modalities, cryoablation induces tumour cell death by osmosis and necrosis. It is hypothesised that with necrosis, the intracellular contents of the cancer cells stay intact allowing the immune system to induce an immune-specific reaction. This immune-specific reaction can, in theory, also affect cancer cells outside the ablated tissue, known as the abscopal effect. Unfortunately, this effect is rarely observed, but when cryoablation is combined with immunotherapy, the effect of both therapies may be enhanced. Although several preclinical studies demonstrated a synergistic effect between cryoablation and immunotherapy, prospective clinical trials are needed to prove this clinical benefit for patients. In this review, we will outline the current evidence for the combination of cryoablation with immunotherapy to treat cancer. [ABSTRACT FROM AUTHOR]

Cancer cells can escape the immune system by different mechanisms. The evasion of cancer cells from immune surveillance is prevented by immune checkpoint inhibitors, allowing the patient's own immune system to attack their cancer. Immune checkpoint inhibitors have shown improvement in overall survival for melanoma, lung cancer and renal cell carcinoma in clinical trials. Unfortunately, not all patients respond to this therapy. In cancer management, percutaneous ablation techniques are well established for both cure and local control of many tumour types. Cryoablation of the tumour tissue results in cell destruction by freezing. Contrary to heat-based ablative modalities, cryoablation induces tumour cell death by osmosis and necrosis. It is hypothesised that with necrosis, the intracellular contents of the cancer cells stay intact allowing the immune system to induce an immune-specific reaction. This immune-specific reaction can, in theory, also affect cancer cells outside the ablated tissue, known as the abscopal effect. Unfortunately, this effect is rarely observed, but when cryoablation is combined with immunotherapy, the effect of both therapies may be enhanced. Although several preclinical studies demonstrated a synergistic effect between cryoablation and immunotherapy, prospective clinical trials are needed to prove this clinical benefit for patients. In this review, we will outline the current evidence for the combination of cryoablation with immunotherapy to treat cancer. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined vemurafenib plasma concentrations in patients with serine/threonine protein kinase B-Raf (BRAF)-mutated melanoma. High performance liquid chromatography-mass spectrometry was used to determine vemurafenib concentrations. Also discussed are patient characteristics, mean treatment duration and dose adjustments.

Background: For patients with metastatic renal cell carcinoma (mRCC), targeted therapies have entered the market since 2006. The aims of this study were to evaluate the uptake and use of targeted therapies for mRCC in The Netherlands, examine factors associated with the prescription of targeted therapies in daily clinical practice and study their effectiveness in terms of overall survival (OS).Methods: Two cohorts from PERCEPTION, a population-based registry of mRCC patients, were used: a 2008-2010 Cohort (n = 645) and a 2011-2013 Cohort (n = 233). Chi-squared tests for trend were used to study time trends in the use of targeted therapy. Patients were grouped based on the eligibility criteria of the SUTENT trial, the trial that led to sunitinib becoming standard of care, to investigate the use of targeted therapies amongst patients fulfilling those criteria. Multi-level logistic regression was used to identify patient subgroups that are less likely to receive targeted therapies.Results: Approximately one-third of patients fulfilling SUTENT trial eligibility criteria did not receive any targeted therapy (29 % in the 2008-2010 Cohort; 35 % in the 2011-2013 Cohort). Patients aged 65+ years were less likely to receive targeted therapy in both cohorts and different risk groups (odds ratios range between 0.84-0.92); other factors like number of metastatic sites were of influence in some subgroups. Amongst treated patients, there was a decreasing trend in sunitinib use over time (p = 0.0061), and an increasing trend in pazopanib use (p = 0.0005).Conclusions: Targeted therapies have largely replaced interferon-alfa as first-line standard of care. Nevertheless, many eligible patients in Dutch daily practice did not receive targeted therapies despite their ability to improve survival. Reasons for their apparent underutilisation should be examined more carefully. [ABSTRACT FROM AUTHOR]

Cellular immunity against cancer can be achieved with viral vector- and DNA-based immunizations. In preclinical studies, cancer vaccines are very potent, but in clinical trials these potencies are not achieved yet. Thus, a rational approach to improve cancer vaccines is warranted. We previously demonstrated that the relatively low intrinsic immunogenicity of DNA vaccines could be enhanced by inclusion of endoplasmic reticulum (ER) targeting and universal helper epitopes within the vaccine. We now evaluated whether an optimal antigen format, as defined in DNA vaccines, can further enhance the effectiveness of recombinant Semliki Forest virus (rSFV) vaccines. To this purpose, we generated, characterized and evaluated the efficacy of rSFV replicon particles expressing human papillomavirus E6 and/or E7 proteins fused to several helper T-cell epitopes and an ER targeting signal. Here, we show that inclusion of a helper cassette and an ER targeting signal enhanced protein stability and markedly augmented the frequencies of human papillomavirus-specific T cells. Even at an immunization dose of as low as 105 replicon particles, this novel vaccine achieved tumor regression and protection. Thus, even highly effective viral vector vaccines can benefit from an improved antigen format, based on the inclusion of defined helper epitopes and ER targeting. [ABSTRACT FROM AUTHOR]

Background:We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials.Methods:Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice.Results:A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%).Conclusion:Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results. [ABSTRACT FROM AUTHOR]

Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml−1 and the patient did not show any grade ⩾3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade ⩾3 toxicity, the sunitinib dose was lowered by 12.5 mg.Results:Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ⩾3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.Conclusions:In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice. [ABSTRACT FROM AUTHOR]

Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)-2, endothelin-1 (ET-1), and endothelium-derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib-induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib-treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC. [ABSTRACT FROM AUTHOR]

The induction of tumor-specific immune responses is largely dependent on the ability of dendritic cells (DCs) to present tumor-associated antigens to T lymphocytes. Therefore, we investigated the use of DC-associated promoter-driven genetic vaccines to specifically target DC in vivo. Restricted expression of vaccine-encoding genes in DC should enhance specificity and improves their safety for clinical applications. Hereto, 3-5 kb upstream sequences of the murine genes encoding CD11c, DC-SIGN, DC-STAMP and Langerin were isolated, characterized and subcloned into enhanced green fluorescent protein (EGFP) reporter constructs. Upon electroporation, EGFP was expressed in DC cell lines, but not in other cell lines, confirming DC-restricted promoter activity. When these promoters were cloned into a construct upstream of the gene for ovalbumin (OVA), it appeared that DC-STAMP promoter-driven expression of OVA (pDCSTAMP/OVA) in DC yielded the most efficient OVA-specific CD4+ and CD8+ T-cell responses in vitro. Administration of pDC-STAMP/OVA in vivo, using the tattoo gun vaccination system, evoked specific immune responses as evidenced in a mouse tumor model. Adoptively transferred pDC-STAMP/OVA-transfected DCs induced strong CD8+ T-cell proliferation in vivo. These experiments demonstrate that our DC-directed promoter constructs are potential tools to restrict antigen expression in DC and could be implemented to modulate DC function by the introduction of relevant proteins. [ABSTRACT FROM AUTHOR]

Background:The endothelin system is involved in tumour growth. Atrasentan, a selective endothelin-A-receptor antagonist, blocks endothelin signalling. This phase I trial studied combining treatment of interferon-alpha (IFN-α) with atrasentan in renal cell carcinoma (RCC).Patients and methods:This study evaluated the safety and tolerance of IFN-α (9MU subcutaneously (s.c.) three times a week) in combination with atrasentan (2.5, 5 and 10 mg orally once daily) in untreated metastatic RCC. Cohort 10 mg was extended to obtain insights in efficacy and pharmacodynamics.Results:Observed toxicities mainly consisted of known IFN-like toxicities (anorexia, chills, fever, fatigue and nausea), and of nasal congestion (associated to atrasentan). None of these toxicities were considered dose limiting. Cohort 10 mg was extended up to 32 patients; in a subset of patients treated according to the protocol (n=27), median overall survival (OS) was 17.3 months. One patient (3.1%) showed a partial response lasting 14.3 months. In an exploratory analysis, we observed that in the subset of patients with declining vascular endothelial growth factor (VEGF) levels (in combination with rising Endothelin-1 levels), median OS was 22.2 months compared with 2.2 months in patients with increasing VEGF levels.Conclusion:Combination treatment of IFN-α 9MU-α s.c. three times a week and atrasentan 10 mg once daily is tolerated. Clinical activity, especially OS, and biomarkers in our view warrant further studies targeting the endothelin axis. [ABSTRACT FROM AUTHOR]

Background. Sunitinib induces partial responses in 47% of patients with metastatic renal cell carcinoma (mRCC). However, the achievement of complete responses remains scarce and all patients will eventually develop progressive disease. Recombinant interleukin-21 (rIL-21) is a novel cytokine, which is believed to deliver sustained cellular anti-tumor response and the combination of both agents may work synergistically. Material and method. From July 2007 to July 2008 in this phase I trial nine therapy-naive patients with metastatic RCC in five European centers were enrolled. Patients with either good or intermediate risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) were eligible without restrictions to histology subtype nor measurable disease. Patients were treated with increasing doses of rIL-21 administered subcutaneously (s.c.) in combination with sunitinib 50 mg once daily (OD) orally at the '4 weeks on/2 weeks off' schedule. Dose-escalation was applied by a conventional '3+3 design'. Planned dose levels (DL) for rIL-21 were 3, 10, 30 and 100 μg/kg s.c. The primary endpoint was to determine the maximum tolerated dose (MTD) and recommended dose (RD). Secondary objectives included pharmacokinetics of sunitinib and rIL-21, and the induction of rIL-21 antibodies. Results. At 10 μg/kg two dose-limiting toxicities (DLT) occurred in four patients, consisting of grade 4 neutropenia and grade 3 thrombocytopenia. The MTD was 3 μg/kg rIL-21 combined with sunitinib 50 mg OD at the '4 weeks on/2 weeks off' schedule. Frequent occurring adverse events were injection site reaction, stomatitis, fatigue and dysgeusia. Conclusions. The combination of sunitinib 50 mg at the '4 weeks on/2 weeks off' schedule and 10 μg/kg IL-21 was not tolerated due to hematological DLTs. The dose level of 3 μg/kg rIL-21 was considered too low to be therapeutically relevant for further evaluation and therefore the study was discontinued. [ABSTRACT FROM AUTHOR]

Natural killer T (NK T) cells play a central role as intermediates between innate and adaptive immune responses important to induce anti-tumour reactivity in cancer patients. In two of 14 renal cell carcinoma (RCC) patients, treated with interferon (IFN)-α, we detected significantly enhanced numbers of circulating NK T cells which were typed phenotypically and analysed for anti-tumour reactivity. These NK T cells were T cell receptor (TCR) Vα24/Vβ11, 6B11 and bound CD1d tetramers. No correlation was observed between NK T frequencies and regulatory T cells (T), which were also enhanced. NK T cells expressed CD56, CD161, CD45RO and CD69 and were predominantly CD8, in contrast to the circulating T cell pool that contained both CD4 and CD8 T cells, as is found in healthy individuals. It is unlikely that IFN-α triggered the high NK T frequency, as all other patients expressed low to normal NK T numbers. A parallel was observed in IFN-α-related increase in activation of NK T cells with that in conventional T and non-T cells. Normal interleukin (IL)-7, IL-12 and IL-15 plasma levels were found. In one of the patients sporadic NK T cells were detected at the tumour site. α-Galactosylceramide (αGalCer) stimulation of peripheral blood mononuclear cells or isolated NK T cell lines from both patients induced IFN-γ, but no IL-4 and no response towards autologous tumour cells or lysates. The clinical course of disease in both patients was not exceptional with regard to histological subtype and extent of metastatic disease. Therefore, despite a constitutive high peripheral frequency and in vitroαGalCer responsiveness, the NK T cells in the two RCC patients did not show anti-tumour responsiveness. [ABSTRACT FROM AUTHOR]

Background: Because sunitinib can induce extensive necrosis in metastatic renal cell cancer (mRCC), we examined whether criteria defined by Choi might be valuable to predict early sunitinib efficacy.Methods: Computed tomography was used for measurement of tumour lesions in mm and lesion attenuation in Hounsfield units (HUs). According to Choi criteria partial response (PR) was defined as > or =10% decrease in size or > or =15% decrease in attenuation.Results: A total of 55 mRCC patients treated with sunitinib were included. At first evaluation, according to the Response Evaluation Criteria in Solid Tumours (RECIST) 7 patients had PR, 38 stable disease (SD), and 10 progressive disease (PD), whereas according to Choi criteria 36 patients had PR, 6 SD and 13 PD. Median tumour attenuation decreased from 66 to 47 HUs (P< or =0.001). In patients with PR, Choi criteria had a significantly better predictive value for progression-free survival and overall survival (both Ps<0.001) than RECIST (P=0.685 and 0.191 respectively). The predictive value for RECIST increased (P=0.001 and <0.001 respectively), when best response during treatment was taken into account.Conclusion: Choi criteria could be helpful to define early mRCC patients who benefit from sunitinib, but the use of these criteria will not change the management of these patients. [ABSTRACT FROM AUTHOR]

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand-foot syndrome and a combination of grade 1-2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of autologous tumor cell vaccinations on the presence and numbers of circulating CD8+ T cells specific for tumor-associated antigens (TAA) in metastatic melanoma patients. To investigate the correlation between the presence of tumor-infiltrating lymphocytes (TIL) and circulating TAA-specific CD8+ T cells before and after autologous tumor cell vaccination with overall survival. Experimental design: Twenty-five stage III and resected stage IV metastatic melanoma patients were adjuvantly treated with a series of intracutaneously injected autologous tumor cell vaccinations, of which the first two contained BCG as an immunostimulatory adjuvant. Tumor samples and blood samples obtained before and after vaccination of these patients were studied for the presence of TAA-specific T cells using HLA-tetramers and results were correlated with survival. Results: In 5 of 17 (29%) melanoma patients, circulating TAA-specific T cells were detectable prior to immunizations. No significant changes in the frequency and specificity were found during the treatment period in all patients. Presence of circulating TAA-specific T cells was not correlated with survival (log rank, P=0.215). Inside melanoma tissue, TAA-specific TIL could be detected in 75% of 16 available tumor samples. In case of detectable TAA-specific TIL, median survival was 22.5 months compared to median survival of 4.5 months in case of absence of TAA-specific T cells (log rank, P=0.0094). In none of the patients, TAA-specific T cells were found both in tumor tissue and blood at the same time. Conclusions: These data suggest that the presence of TAA-specific TILs forms a prognostic factor, predicting improved survival in advanced-stage melanoma patients. The absence of TAA-specific T cells in the circulation suggests that homing of the tumor-specific T cell population to the tumor site contributes to the effectiveness of antitumor immunity. [ABSTRACT FROM AUTHOR]

Metastatic renal cell cancer is one of the immuno-sensitive tumors. Apart from the immuno-modulating agents IFNα and IL-2, thalidomide has been reported to be effective in this type of cancer. However, bone metastases and bulky metastases, show limited response to immunotherapy, are often site of recurrent disease and are therefore often treated later with radiotherapy. In this phase II study, we evaluated toxicity and efficacy of the combination of continuous low dose (1 mIU/m2) s.c. IL-2 and thalidomide (200 mg once daily) in 22 patients with progressive metastatic renal cell cancer. In addition, 13 soft tissue lesions and two bone metastases in 13 patients were concurrently treated with fractionated radiotherapy. T cell number and activation in blood was measured by immunoflowcytometry. Nearly all patients developed grade 1–2 toxicity consisting of fatigue, sensory neuropathy, constipation and dizziness. Five patients had a grade 3–4 toxic event: four patients with deep venous thrombosis requiring anticoagulant therapy, and one patient who developed radiation myelopathy. On systemic response evaluation ten patients showed ongoing SD with a mean progression free survival of 9 months. One patient showed a PR (at an irradiated site). Regarding local response to irradiation, seven lesions showed a PR for a mean time period of 8.7 months, whereas seven were stable for 6 months. The radiation response of one lesion was not evaluable. Immunoflowcytometry showed an increase in number and activation of lymphocytes (mainly Natural Killer—NK-cells), which was absent or even decreased in irradiated patients. The combination of sc. low dose IL-2, thalidomide and radiotherapy is feasible, but relatively toxic and does not lead to higher responses at non-irradiated sites. The combination of immunotherapy and concurrent radiotherapy is effective at 60% of the relatively large evaluable sites. Progressive myelopathy developed in one patient, possibly due to radiotherapy in combination with thalidomide. [ABSTRACT FROM AUTHOR]

This report describes an effective method for the cloning of Mycobacterium leprae-reactive T lymphocytes with Epstein-Barr-virus transformed autologous B cells as antigen-presenting cells. The two advantages of this method are that it drastically reduces the number of autologous peripheral blood mononuclear cells (<107 cells) needed to obtain and propagate these T-cell clones (TLC), and that it enables us to expand individual TLC to large numbers of cells (>108). Thus the major obstacles for the cloning of T lymphocytes-especially important with regard to patient-are bypassed. Thus far, TLC from three leprosy patients have been established. These TLC are HLA class II restricted in their M. leprae-directed response. A marked enhancement in antigen responsiveness was observed after further expansion of several TLC, some of which turned from nonresponder into responder TLC. Four tested TLC display strikingly different antigen recognition patterns when tested against a number of other mycobacterial antigens; one TLC so far recognizes only M. leprae antigens. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a study which found that flt-3 polymorphism is associated with the risk of having leukopenia following treatment with sunitinib.

A response to a letter to the editor about the article "Predictive Factors for Severe Toxicity of Sunitinib in Unselected Patients With Advanced Renal Cell Cancer" is presented.