Browsing by Subject "IMMUNOTHERAPY"

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  • Havunen, Riikka; Santos, Joao M.; Sorsa, Suvi; Rantapero, Tommi; Lumen, Dave; Siurala, Mikko; Airaksinen, Anu J.; Cervera-Carrascon, Victor; Tähtinen, Siri; Kanerva, Anna; Hemminki, Akseli (2018)
    Cancer treatment with local administration of armed oncolytic viruses could potentially induce systemic antitumor effects, or the abscopal effect, as they self-amplify in tumors, induce danger signaling, and promote tumor-associated antigen presentation. In this study, oncolytic adenovirus coding for human tumor necrosis factor alpha (TNF-alpha) and interleukin-2 (IL-2) Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 (also known as [a.k.a.] TILT-123) provoked antitumor efficacy in tumors that were injected with Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 and those that were left non-injected in the same animal. Importantly, the virus was able to travel to distant tumors. To dissect the effects of oncolysis and cytokines, we studied replication-incompetent viruses in mice. Systemic antitumor effects were similar in both models, highlighting the importance of the arming device. The cytokines induced positive changes in immune cell infiltrates and induced the expression of several immune-reaction-related genes in tumors. In addition, Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 was able to increase homing of adoptively transferred tumor-infiltrating lymphocytes into both injected and non-injected tumors, possibly mediated through chemokine expression. In summary, local treatment with Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 resulted in systemic antitumor efficacy by inducing immune cell infiltration and trafficking into both treated and untreated tumors. Moreover, the oncolytic adenovirus platform had superior systemic effects over replication-deficient vector through spreading into distant tumors.
  • Kasanen, Henna; Hernberg, Micaela; Mäkelä, Siru; Brück, Oscar; Juteau, Susanna; Kohtamäki, Laura; Ilander, Mette; Mustjoki, Satu; Kreutzman, Anna (2020)
    Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naive metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease
  • Kuryk, Lukasz; Moller, Anne-Sophie W.; Garofalo, Mariangela; Cerullo, Vincenzo; Pesonen, Sari; Alemany, Ramon; Jaderberg, Magnus (2018)
    Oncolytic adenoviral immunotherapy activates the innate immune system with subsequent induction of adaptive tumor-specific immune responses to fight cancer. Hence, oncolytic viruses do not only eradicate cancer cells by direct lysis, but also generate antitumor immune response, allowing for long-lasting cancer control and tumor reduction. Their therapeutic effect can be further enhanced by arming the oncolytic adenovirus with costimulatory transgenes and/or coadministration with other antitumor therapies. ONCOS-102 has already been found to be well tolerated and efficacious against some types of treatment-refractory tumors, including mesothelin-positive ovarian cancer (NCT01598129). It induced local and systemic CD8+ T-cell immunity and upregulated programmed death ligand 1. These results strongly advocate the use of ONCOS-102 in combination with other therapeutic strategies in advanced and refractory tumors, especially those expressing the mesothelin antigen. The in vivo work presented herein describes the ability of the oncolytic adenovirus ONCOS-102 to induce mesothelin-specific T-cells after the administration of the virus in bagg albino (BALB/c) mice with mesothelin-positive tumors. We also demonstrate the effectiveness of the interferon-gamma the enzyme-linked immunospot (ELISPOT) assay to detect the induction of T-cells recognizing mesothelin, hexon, and E1A antigens in ONCOS-102treated mesothelioma-bearing BALB/c mice. Thus, the ELISPOT assay could be useful to monitor the progress of therapy with ONCOS-102.
  • Pahr, Sandra; Selb, Regina; Weber, Milena; Focke-Tejkl, Margarete; Hofer, Gerhard; Dordic, Andela; Keller, Walter; Papadopoulos, Nikolaos G.; Giavi, Stavroula; Makela, Mika; Pelkonen, Anna; Niederberger, Verena; Vrtala, Susanne; Valenta, Rudolf (2014)
  • Koski, Anniina; Bramante, Simona; Kipar, Anja; Oksanen, Minna; Juhila, Juuso; Vassilev, Lotta; Joensuu, Timo; Kanerva, Anna; Hemminki, Akseli (2015)
    In clinical trials with oncolytic adenoviruses, there has been no mortality associated with treatment vectors. Likewise, in the Advanced Therapy Access Program (ATAP), where 290 patients were treated with 10 different viruses, no vector-related mortality was observed. However, as the patient population who received adenovirus treatments in ATAP represented heavily pretreated patients, often with very advanced disease, some patients died relatively soon after receiving their virus treatment mandating autopsy to investigate cause of death. Eleven such autopsies were performed and confirmed disease progression as the cause of death in each case. The regulatory requirement for investigating the safety of advanced therapy medical products presented a unique opportunity to study tissue samples collected as a routine part of the autopsies. Oncolytic adenoviral DNA was recovered in a wide range of tissues, including injected and noninjected tumors and various normal tissues, demonstrating the ability of the vector to disseminate through the vascular route. Furthermore, we recovered and cultured viable virus from samples of noninjected brain metastases of an intravenously treated patient, confirming that oncolytic adenovirus can reach tumors through the intravascular route. Data presented here give mechanistic insight into mode of action and biodistribution of oncolytic adenoviruses in cancer patients.
  • Kanerva, Anna; Koski, Anniina; Liikanen, Ilkka; Oksanen, Minna; Joensuu, Timo; Hemminki, Otto; Palmgren, Juni; Hemminki, Kari; Hemminki, Akseli (2015)
  • MASK Study GroupJr; Bedard, Annabelle; Anto, Josep M.; Fonseca, Joao A.; Toppila-Salmi, Sanna; Basagana, Xavier (2020)
    Background In allergic rhinitis, a relevant outcome providing information on the effectiveness of interventions is needed. In MASK-air (Mobile Airways Sentinel Network), a visual analogue scale (VAS) for work is used as a relevant outcome. This study aimed to assess the performance of the work VAS work by comparing VAS work with other VAS measurements and symptom-medication scores obtained concurrently. Methods All consecutive MASK-air users in 23 countries from 1 June 2016 to 31 October 2018 were included (14 189 users; 205 904 days). Geolocalized users self-assessed daily symptom control using the touchscreen functionality on their smart phone to click on VAS scores (ranging from 0 to 100) for overall symptoms (global), nose, eyes, asthma and work. Two symptom-medication scores were used: the modified EAACI CSMS score and the MASK control score for rhinitis. To assess data quality, the intra-individual response variability (IRV) index was calculated. Results A strong correlation was observed between VAS work and other VAS. The highest levels for correlation with VAS work and variance explained in VAS work were found with VAS global, followed by VAS nose, eye and asthma. In comparison with VAS global, the mCSMS and MASK control score showed a lower correlation with VAS work. Results are unlikely to be explained by a low quality of data arising from repeated VAS measures. Conclusions VAS work correlates with other outcomes (VAS global, nose, eye and asthma) but less well with a symptom-medication score. VAS work should be considered as a potentially useful AR outcome in intervention studies.
  • Tahtinen, Siri; Kaikkonen, Saija; Merisalo-Soikkeli, Maiju; Gronberg-Vaha-Koskela, Susanna; Kanerva, Anna; Parviainen, Suvi; Vaha-Koskela, Markus; Hemminki, Akseli (2015)
    Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16. OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-alpha 2, IFN-gamma, TNF-alpha, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-alpha 2, IFN-gamma and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-alpha 2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-alpha 2, IFN-gamma and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience.
  • Hirvinen, Mari; Heiskanen, Raita; Oksanen, Minna; Pesonen, Saila; Liikanen, Ilkka; Joensuu, Timo; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli (2013)
  • Landry, M. R.; DuRoss, A. N.; Neufeld, M. J.; Hahn, L.; Sahay, G.; Luxenhofer, R.; Sun, C. (2020)
    Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both in vitro and in vivo in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.
  • Sammallahti, Heidelinde; Kokkola, Arto; Rezasoltani, Sama; Ghanbari, Reza; Asadzadeh Aghdaei, Hamid; Knuutila, Sakari; Puolakkainen, Pauli; Sarhadi, Virinder Kaur (2021)
    Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.
  • Ylösmäki, Erkko; Fusciello, Manlio; Martins, Beatriz; Feola, Sara; Hamdan, Firas; Chiaro, Jacopo; Ylösmäki, Leena; Vaughan, Matthew J.; Viitala, Tapani; Kulkarni, Prasad S.; Cerullo, Vincenzo (2021)
    Background Intratumoral BCG therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumor. However, an increase in the number of BCG-induced tumor-specific T cells in the tumor microenvironment could lead to enhanced therapeutic effects. Methods Here, we have developed a novel cancer vaccine platform based on BCG that can broaden BCG-induced immune responses to include tumor antigens. By physically attaching tumor-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoral T cell-specific immune responses toward the attached tumor antigens. These therapeutic peptides can be efficiently attached to the mycobacterial outer membrane using a poly-lysine sequence N-terminally fused to the tumor-specific peptides. Results Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the antitumor immune responses of BCG could be improved by coating the BCG with tumor-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-programmed death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy, the number of responders to anti-PD-1 immunotherapy was markedly increased. Conclusions This study shows that intratumoral BCG immunotherapy can be improved by coating the bacteria with modified tumor-specific peptides. In addition, this improved BCG immunotherapy can be combined with ICI therapy to obtain enhanced tumor growth control. These results warrant clinical testing of this novel cancer vaccine platform.
  • Liikanen, Ilkka; Basnet, Saru; Quixabeira, Dafne C. A.; Taipale, Kristian; Hemminki, Otto; Oksanen, Minna; Kankainen, Matti; Juhila, Juuso; Kanerva, Anna; Joensuu, Timo; Tähtinen, Siri; Hemminki, Akseli (2022)
    Background Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. Methods Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3 increment 24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher's test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. Results Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. Conclusions Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.
  • Zafar, Sadia; Basnet, Saru; Launonen, Inga-Maria; Quixabeira, Dafne Carolina Alves; Santos, Joao; Hemminki, Otto; Malmstedt, Minna; Cervera-Carrascon, Victor; Aronen, Pasi; Kalliokoski, Riikka; Havunen, Riikka; Rannikko, Antti; Mirtti, Tuomas; Matikainen, Mika; Kanerva, Anna; Hemminki, Akseli (2021)
    Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.
  • Havunen, Riikka; Siurala, Mikko; Sorsa, Suvi; Gronberg-Vaha-Koskela, Susanna; Behr, Michael; Tähtinen, Siri; Santos, Joao Manuel; Karell, Pauliina; Rusanen, Juuso; Nettelbeck, Dirk M.; Ehrhardt, Anja; Kanerva, Anna; Hemminki, Akseli (2017)
    Adoptive cell therapy holds much promise in the treatment of cancer but results in solid tumors have been modest. The notable exception is tumor-infiltrating lymphocyte (TIL) therapy of melanoma, but this approach only works with high-dose preconditioning chemotherapy and systemic interleukin (IL)-2 postconditioning, both of which are associated with toxicities. To improve and broaden the applicability of adoptive cell transfer, we constructed oncolytic adenoviruses coding for human IL-2 (hIL2), tumor necrosis factor alpha (TNF-alpha), or both. The viruses showed potent antitumor efficacy against human tumors in immunocompromised severe combined immunodeficiency (SCID) mice. In immunocompetent Syrian hamsters, we combined the viruses with TIL transfer and were able to cure 100% of the animals. Cured animals were protected against tumor re-challenge, indicating a memory response. Arming with IL-2 and TNF-alpha increased the frequency of both CD4(+) and CD8(+) TILs in vivo and augmented splenocyte proliferation ex vivo, suggesting that the cytokines were important for T cell persistence and proliferation. Cytokine expression was limited to tumors and treatment-related signs of systemic toxicity were absent, suggesting safety. To conclude, cytokine-armed oncolytic adenoviruses enhanced adoptive cell therapy by favorable alteration of the tumor microenvironment. A clinical trial is in progress to study the utility of Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123) in human patients with cancer.
  • Kuryk, Lukasz; Moller, Anne-Sophie W.; Vuolanto, Antti; Pesonen, Sari; Garofalo, Mariangela; Cerullo, Vincenzo; Jaderberg, Magnus (2019)
    Oncolytic adenoviruses can trigger lysis of tumor cells, induce an antitumor immune response, bypass classical chemotherapeutic resistance strategies of tumors, and provide opportunities for combination strategies. A major challenge is the development of scalable production methods for viral seed stocks and sufficient quantities of clinical grade viruses. Because of promising clinical signals in a compassionate use program (Advanced Therapy Access Program) which supported further development, we chose the oncolytic adenovirus ONCOS-401 as a testbed for a new approach to scale up. We found that the best viral production conditions in both T-175 flasks and HYPERFlasks included A549 cells grown to 220,000 cells/cm(2) (80% confluency), with ONCOS-401 infection at 30 multiplicity of infection (MOI), and an incubation period of 66 h. The Lysis A harvesting method with benzonase provided the highest viral yield from both T-175 and HYPERFlasks (10,887 +/- 100 and 14,559 +/- 802 infectious viral particles/cell, respectively). T-175 flasks and HYPERFlasks produced up to 2.1 x 10(9) +/- 0.2 and 1.75 x 10(9) +/- 0.08 infectious particles of ONCOS-401 per cm(2) of surface area, respectively. Our findings suggest a suitable stepwise process that can be applied to optimizing the initial production of other oncolytic viruses.
  • Äyräväinen, Leena; Leirisalo-Repo, Marjatta; Kuuliala, Antti; Ahola, Kirsi; Koivuniemi, Riitta; Meurman, Jukka H.; Heikkinen, Anna Maria (2017)
    Objectives To investigate the association between rheumatoid arthritis (RA) and periodontitis with special emphasis on the role of antirheumatic drugs in periodontal health. Design Prospective follow-up study. Patients with early untreated RA and chronic active RA were examined at baseline and 16months later. Controls were examined once. Settings and participants The study was conducted in Finland from September 2005 to May 2014 at the Helsinki University Hospital. Overall, 124 participants were recruited for dental and medical examinations: 53 were patients with early disease-modifying antirheumatic drug (DMARD) na1ve RA (ERA), 28 were patients with chronic RA (CRA) with insufficient response to conventional DMARDs. After baseline examination, patients with ERA started treatment with synthetic DMARDs and patients with CRA with biological DMARDs. Controls were 43 age-matched, gender-matched and community-matched participants. Outcome measures Degree of periodontitis (defined according to the Center for Disease Control and Prevention and the American Academy of Periodontology). Prevalence of periodontal bacteria (analysed from plaque samples), clinical rheumatological status by Disease Activity Score, 28-joint count (DAS28), function by Health Assessment Questionnaire (HAQ) and treatment response by European League Against Rheumatism (EULAR) criteria. Results Moderate periodontitis was present in 67.3% of patients with ERA, 64.3% of patients with CRA and 39.5% of control participants (p=0.001). Further, patients with RA had significantly more periodontal findings compared with controls, recorded with common periodontal indexes. In the re-examination, patients with RA still showed poor periodontal health in spite of treatment with DMARDs after baseline examination. The prevalence of Porphyromonas gingivalis was higher in patients with ERA with periodontal probing depth 4mm compared with patients with CRA and controls. Antirheumatic medication did not seem to affect the results. Conclusions Moderate periodontitis was more frequent in patients with RA than in controls. Patients with ERA and CRA exhibited poorer periodontal health parameters when compared with controls. There was no association between antirheumatic treatment and periodontal parameters.
  • ARIA EPOS Working Groups; Haahtela, Tari (2017)
    Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second-level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long-term therapeutic strategy. Endotype-driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment.
  • Schmidt, Marcus; Weyer-Elberich, Veronika; Hengstler, Jan G.; Heimes, Anne-Sophie; Almstedt, Katrin; Gerhold-Ay, Aslihan; Lebrecht, Antje; Battista, Marco J.; Hasenburg, Annette; Sahin, Ugur; Kalogeras, Konstantine T.; Kellokumpu-Lehtinen, Pirkko-Liisa; Fountzilas, George; Wirtz, Ralph M.; Joensuu, Heikki (2018)
    Background: The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer. Methods: The study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2)-positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and their influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation. Results: High CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29-0.67, P Conclusions: The results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC.
  • Peltonen, Karita; Feola, Sara; Umer, Husen M.; Chiaro, Jacopo; Mermelekas, Georgios; Ylösmaki, Erkko; Pesonen, Sari; Branca, Rui M. M.; Lehtiö, Janne; Cerullo, Vincenzo (2021)
    Simple Summary Immunotherapy has revolutionized cancer treatment, yet many tumors remain resistant to current immuno-oncology therapies. Here we explore a novel, customized oncolytic adenovirus vaccine platform as immunotherapy in a resistant tumor model. We present a workflow for customizing the oncolytic vaccine for improved tumor targeting. This targeting is based on experimentally discovered tumor antigens, which are incorporated as active components of the vaccine formulation. The pipeline may be further applied for designing personalized therapeutic cancer vaccines. Knowledge of clinically targetable tumor antigens is becoming vital for broader design and utility of therapeutic cancer vaccines. This information is obtained reliably by directly interrogating the MHC-I presented peptide ligands, the immunopeptidome, with state-of-the-art mass spectrometry. Our manuscript describes direct identification of novel tumor antigens for an aggressive triple-negative breast cancer model. Immunopeptidome profiling revealed 2481 unique antigens, among them a novel ERV antigen originating from an endogenous retrovirus element. The clinical benefit and tumor control potential of the identified tumor antigens and ERV antigen were studied in a preclinical model using two vaccine platforms and therapeutic settings. Prominent control of established tumors was achieved using an oncolytic adenovirus platform designed for flexible and specific tumor targeting, namely PeptiCRAd. Our study presents a pipeline integrating immunopeptidome analysis-driven antigen discovery with a therapeutic cancer vaccine platform for improved personalized oncolytic immunotherapy.