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| 2. |
- Derksen, Jeroen W. G., et al.
(author)
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European practice patterns and barriers to smoking cessation after a cancer diagnosis in the setting of curative versus palliative cancer treatment
- 2020
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 138, s. 99-108
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Journal article (peer-reviewed)abstract
- Background: Smoking cessation after a cancer diagnosis is associated with improved overall survival. Few studies have reported oncologists' cessation practice patterns, but differences between the curative and palliative settings have not been described. We aimed to study the oncologist's perceptions on patients' tobacco use, current practices and barriers to providing smoking cessation support, while distinguishing between treatment with curative (C) and palliative (P) intent.Methods: In 2019, an online 34-item survey was sent to approximately 6235 oncologists from 16 European countries. Responses were descriptively reported and compared by treatment setting.Results: Responses from 544 oncologists were included. Oncologists appeared to favour addressing tobacco in the curative setting more than in the palliative setting. Oncologists believe that continued smoking impacts treatment outcomes (C: 94%, P: 74%) and that cessation support should be standard cancer care (C: 95%, P: 63%). Most routinely assess tobacco use (C: 93%, P: 78%) and advise patients to stop using tobacco (C: 88%, P: 54%), but only 24% (P)–39% (C) routinely discuss medication options, and only 18% (P)–31% (C) provide cessation support. Hesitation to remove a pleasurable habit (C: 13%, P: 43%) and disbelieve on smoking affecting outcomes (C: 3%, P: 14%) were disparate barriers between the curative and palliative settings (p < 0.001), but dominant barriers of time, resources, education and patient resistance were similar between settings.Conclusion: Oncologists appear to favour addressing tobacco use more in the curative setting; however, they discuss medication options and/or provide cessation support in a minority of cases. All patients who report current smoking should have access to evidence-based smoking cessation support, also patients treated with palliative intent given their increasing survival.
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| 3. |
- Elfving, Hedvig, et al.
(author)
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Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer
- 2021
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In: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 151, s. 53-59
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Journal article (peer-reviewed)abstract
- Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1-3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort.Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis.Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression.Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.
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- Eltahir, mohmo394, et al.
(author)
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Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients
- 2021
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In: International Immunopharmacology. - : Elsevier. - 1567-5769 .- 1878-1705. ; 90
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Journal article (peer-reviewed)abstract
- Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods. To better recapitulate an in vivo setting, we implemented a unique human whole blood "loop" system to study patient-specific immune responses to rituximab in blood derived from CLL patients. Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature. Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting.
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| 5. |
- Eltahir, Mohamed
(author)
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Antibody-based Cancer Immunotherapy : Personalization, response prediction and safety considerations
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Antibody-based therapeutics have remarkably improved the field of immuno-oncology. Multiple monoclonal antibodies (mAbs) are approved for clinical use, and numerous antibodies are under clinical development. The scope of this thesis is to study the personalization of antibody-based immunotherapeutics and tools to predict their efficacy and safety.In paper I, we investigated a new method for predicting immune toxicity related to mAbs infusion, the whole blood loop assay (WBLA). The assay recapitulates the in vivo setting and harmonizes well with clinically validated cytokine release assays (CRAs) following agonistic mAbs infusion. We also demonstrated the robustness of the assay in studying complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).Rituximab, the first approved mAb for an oncology indication, is known to induce CRS occasionally. In paper II, the WBLA was used to profile the chronic lymphocytic leukemia (CLL) patients’ specific responses to rituximab infusion. We demonstrated rituximab-induced CRS profile and complement activation in blood from CLL patients but not in blood from healthy donors. We also noted that NK cells were a significant source of the rituximab-induced cytokine release. Using Fc mutant versions of rituximab, the mode-of-action of rituximab in whole blood with respect to CDC and ADCC was elaborated.In paper III, we presented a novel flexible peptide cancer vaccine platform based on an anti-CD40 agonistic antibody. The platform consists of a bispecific antibody targeting CD40 and peptide-tagged antigens. The bispecific antibody retained the agonistic activity of anti-CD40 and was superior to parental anti-CD40 mAb in targeting antigen cross-presentation and stimulating both CD8+ and CD4+ T cell responses.In paper IV, we investigated the feasibility of proximity-extension assay (PEA) plasma proteomic analysis in predicting response to checkpoint inhibitors (CPIs) in non-small cell lung cancer patients. CPIs show great success in the clinic. However, not all patients benefit from CPIs. Using an immuno-oncology protein panel, we demonstrated that high plasma levels of T cell activation proteins were associated with better survival. We also identified an association between the pre-CPI plasma levels of CXCL9, CXCL10, IL-15, ADA and Casp8 and the response to CPI therapy. In conclusion, this thesis demonstrates the feasibility of using the WBLA to assess antibody infusion efficacy and safety, as well as PEA plasma proteomics to predict response to CPI therapy. Additionally, it presents a novel approach for personalized therapeutic cancer vaccine delivery.
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| 6. |
- Helgadottir, H., et al.
(author)
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Survival after introduction of adjuvant treatment in stage III melanoma: a nationwide registry-based study
- 2023
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In: Jnci-Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 41:16
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Journal article (peer-reviewed)abstract
- Background Adjuvant treatments with PD-1 and BRAF+MEK inhibitors statistically significantly prolong recurrence-free survival in stage III cutaneous melanoma. Yet, the effect on overall survival is still unclear. Based on recurrence-free survival outcomes, these treatments have been approved and widely implemented. The treatments have considerable side effects and costs, and overall survival effect remains a highly anticipated outcome. Methods Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage III melanoma between 2016 and 2020. The patients were divided depending on if they were diagnosed before or from July 2018, based on the timepoint when adjuvant treatment was introduced in Sweden. Patients were followed up until the end of 2021. In this cohort study, melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox-regression analyses. Results There were 1371 patients diagnosed with stage III primary melanoma in Sweden in 2016-2020. The 2-year overall survival rates, comparing the 634 patients in the precohort and the 737 in the postcohort, were 84.3% (95% confidence interval [CI] = 81.4% to 87.3%) and 86.1% (95% CI = 83.4% to 89.0%), respectively, with an adjusted hazard ratio of 0.91 (95% CI = 0.70 to 1.19, P = .51). Further, no statistically significant overall or melanoma-specific survival differences were seen when comparing the precohort and the postcohort in different subgroups for age, sex, or tumor characteristics. Conclusions In this nationwide population-based and registry-based study, no survival benefit was detected in patients diagnosed before or after the implementation of adjuvant treatment in stage III melanoma. These findings encourage a careful assessment of the current recommendations on adjuvant treatment.
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| 8. |
- Irenaeus, Sandra, 1984-
(author)
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Intratumoral CD40 stimulating therapy in patients with advanced cancer
- 2021
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Doctoral thesis (other academic/artistic)abstract
- CD40-CD40L interaction activates DCs to become highly efficient APCs and skews the adaptive immune response towards a Th I phenotype driving cytotoxic T cells, M1 macrophages and natural killer cells. Furthermore, engagement of CD40L to CD40 positive cancer cells can have direct anti-proliferative effects, induce apoptosis and increase expression of MHC and other co-stimulatory molecules, thereby enhancing cancer cell recognition. Hence, activating the CD40-CD40L pathway may lead to several potential anti-tumoral effects. In this thesis we evaluated activation of the CD40-CD40L pathway in patients with solid cancer by investigating three medicinal products administered mainly through intratumoral injection: ADC1013 - an agonistic CD40 antibody, AdCD40L - a replication deficient adenovirus carrying the gene for CD40L and LOAd703 - an oncolytic adenovirus carrying two immunostimulatory genes: TMZ-CD40L and 4-1BBL. In paper I, ADC-1013 was investigated in patients with metastatic cancer (n=23) in a phase I trial. ADC-1013 was injected intratumorally (n=18) or intravenously (n=5). AdCD40L was investigated in a phase I/II study reported in paper II and III, respectively. In one cohort (paper II), patients with metastatic malignant melanoma (n=9) were treated with four weekly intratumoral injections with AdCD40L preceded by radiotherapy (single fraction 8 Gy) of the metastasis to subsequently be injected. Concomitant low dose cyclophosphamide was administered before the first and fourth intratumoral injection. In another cohort (paper III), patients with metastatic non melanoma solid cancer (n=6) were treated with the same schedule except from radiotherapy. Paper III also reports the results of the first-ever patient treated with AdCD40L. In paper IV, the preliminary results of phase I of a phase I/II study investigating LOAd703 administered intratumorally at a two-week interval are presented. LOAd703 was given as an add-on to standard-of-care chemotherapy, or with gemcitabine conditioning in patients having received established treatments. Patients (n=9) had locally advanced or metastatic pancreatic cancer, metastatic ovarian cancer or colorectal cancer. We conclude that treatment with all three medicinal products was safe and tolerable. For ADC-1013, the therapeutic ratio seemed to be more favorable for intratumoral injections into superficial metastases compared to deep metastases. We demonstrated that AdCD40L can be combined with radiotherapy without increasing toxicity although radiotherapy did not enhance treatment efficacy. Further, LOAd703 was safe to combine with chemotherapy. Although the number of patients treated in each trial was limited, and almost all patients were considered refractory to standard treatment at inclusion, some patients seemed to benefit from treatment which is encouraging.
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| 9. |
- Irenaeus, Sandra, et al.
(author)
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Intratumoral immunostimulatory AdCD40L gene therapy in patients with advanced solid tumors.
- 2021
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In: Cancer Gene Therapy. - : Springer Science and Business Media LLC. - 0929-1903 .- 1476-5500. ; 28:10-11, s. 1188-1197
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Journal article (peer-reviewed)abstract
- AdCD40L is a replication-deficient virus carrying the gene for CD40 ligand which has previously been evaluated in patients with urothelial cancer and malignant melanoma. Herein, we present the results of repeated intratumoral injections of AdCD40L in seven patients with metastatic solid cancer. One patient who developed urothelial cancer derived from a renal transplant was treated with repeated injections of AdCD40L alone. The remaining patients suffered from cholangiocarcinoma, kidney, breast, rectal, or ovarian cancer and received AdCD40L repeatedly (4x) in combination with cyclophosphamide. The treatment was safe and generally well-tolerated. Two patients had clinical benefit of the treatment and one of them was accepted for re-treatment. Circulating proinflammatory cytokines were commonly increased after treatment, but save for TNFα, significances were not reached which could be due to the low number of patients. Similar to earlier findings in AdCD40L-treated melanoma patients, IL8 plasma levels were high in the present study. In conclusion, gene therapy by repeated intratumoral AdCD40L injections alone, or in combination with cyclophosphamide, is feasible and safe in patients with solid cancers. The potential of intratumoral CD40L gene transfer as treatment of cancer was illustrated by the clinical improvement in two out of seven patients.
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| 10. |
- Johansson, Anna L., V, et al.
(author)
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Cancer survival in women diagnosed with pregnancy-associated cancer : An overview using nationwide registry data in Sweden 1970-2018
- 2021
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In: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 155, s. 106-115
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Journal article (peer-reviewed)abstract
- Background: Pregnancy-associated cancer (PAC) is increasing over time in many countries. We provide a comprehensive, population-based overview of cancer survival in women with PAC across five decades.Methods: We performed a nationwide cohort study of 121,382 women diagnosed with cancer at age 15-49 between 1970 and 2018 using birth and cancer registers in Sweden. Pregnancy associated cancer was defined as diagnosed during pregnancy and within one year of delivery, while non-PAC was outside this window. Cox regression estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing cancer mortality for PAC versus non-PAC.Results: In total, 5079 women had a diagnosis of PAC. Cutaneous malignant melanoma, breast, cervical, thyroid and central nervous system (CNS) were the most common sites of PAC. A higher cancer mortality was observed in PAC versus non-PAC for breast (HR = 1.72, 95% CI 1.54-1.93) and uterine cancer (myometrium/unspecified) (8.62, 2.80-26.53), in which all PAC deaths were uterine sarcomas. Increased mortality was also observed in upper digestive tract cancer diagnosed during pregnancy and colon cancer diagnosed during first year after delivery. Contrary, the HR for CNS tumours was significantly decreased (0.71, 0.55-0.91). Survival after PAC improved for most sites over time, with survival after breast cancer during pregnancy in recent years being similar to that of non-pregnancy associated breast cancer.Conclusion: For the majority of sites, PAC was not associated with poorer prognosis compared to non-PAC, a finding which was stable over time. The main exceptions were breast cancer and rarer cancers, such as uterine sarcoma.
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