The present study reports the case of a patient with hormone-refractory metastatic prostate cancer who had failed standard therapy, but then achieved complete remission following combined treatment with local hyperthermia (LHT), Newcastle disease virus and dendritic cell (DC) vaccination, which was an unusual combination. In August 2005, the patient underwent a radical prostatectomy. Despite standard treatment, the patient developed progressive bone metastases and stopped conventional therapy in June 2007. Starting in October 2007, the patient was treated with LHT, oncolytic virotherapy and DC vaccination. Prostate-specific antigen (PSA)-levels, with the highest level of 233.8 ng/ml in January 2008, decreased to 0.8 ng/ml in late February 2008. In March 2008, a reduction in bone metastases could be detected by positron emission tomography/computed tomography. Since then, the PSA levels have remained low and the patient is doing well. The treatment induced a long-lasting antitumor memory T-cell response. This possibly explains the long-term effectiveness of this novel experimental combined treatment approach.
Liver metastases in breast cancer are associated with a poor prognosis. We report long-term survival of a patient with breast cancer and liver metastases. After operation the patient declined further standard therapy. Instead, she was treated with local hyperthermia, Newcastle disease virus and dendritic cell vaccination at the Immunological and Oncological Center Cologne (IOZK), Germany. A continuous high quality of life was reported and the patient survived more than 66 months after initial diagnosis. No recurrence or further metastases developed under treatment. Following treatment, a long-lasting tumor-reactive memory T-cell responsiveness could be documented. This possibly explains the favorable course of disease. Since this combination of therapies is not restricted to a particular tumor type, further exploration is warranted.
Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor–host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor–host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system.
The fundamental aim of healthcare is to improve overall health of the population by providing state-of-the-art healthcare for individuals at an affordable cost. The foundation for this system is largely referred to as “evidence-based medicine”. Too often, evidence-based medicine is based solely on so-called “best research evidence”, collected through randomized controlled trials while disregarding clinical expertise and patient expectations. As healthcare gravitates towards personalized and individualized medicine, such external clinical (research) evidence can inform, but never replace, individual clinical expertise. This applies in particular to orphan diseases, for which clinical trials are methodologically particularly problematic, and evidence derived from them is often questionable. Evidence-based medicine constitutes a complex process to allow doctors and patients to select the best possible solutions for each individual based on rapidly developing new therapeutic directions. This requires a revisit of the foundations of evidence-based medicine. A proposition as to how to manage evidence-based data in individualized immune-oncology is presented here.
At times of personalized and individualized medicine the concept of randomized- controlled clinical trials (RCTs) is being questioned. This review article explains principles of evidence-based medicine in oncology and shows an example of how evidence can be generated independently from RCTs. Personalized medicine involves molecular analysis of tumor properties and targeted therapy with small molecule inhibitors. Individualized medicine involves the whole patient (tumor and host) in the context of immunotherapy. The example is called Individualized Multimodal Immunotherapy (IMI). It is based on the individuality of immunological tumor–host interactions and on the concept of immunogenic tumor cell death (ICD) induced by an oncolytic virus. The evidence is generated by systematic data collection and analysis. The outcome is then shared with the scientific and medical community. The priority of big pharma studies is commercial benefit. Methods used to achieve this are described and have damaged the image of RCT studies in general. A critical discussion is recommended between all partners of the medical health system with regard to the conduct of RCTs by big pharma companies. Several clinics and institutions in Europe try to become more independent from pharma industry and to develop their own modern cancer therapeutics. Medical associations should include references to such studies from personalized and individualized medicine in their guidelines.
Synergistic activity between maintenance temozolomide (TMZm) and individualized multimodal immunotherapy (IMI) during/after first-line treatment has been suggested to improve the overall survival (OS) of adults with IDH1 wild-type MGMT promoter-unmethylated (unmeth) GBM. We expand the data and include the OS of MGMT promoter-methylated (meth) adults with GBM. Unmeth (10 f, 18 m) and meth (12 f, 10 m) patients treated between 27 May 2015 and 1 January 2022 were analyzed retrospectively. There were no differences in age (median: 48 y) or Karnofsky performance index (median: 80). The IMI consisted of 5-day immunogenic cell death (ICD) therapies during TMZm: Newcastle disease virus (NDV) bolus injections and sessions of modulated electrohyperthermia (mEHT); subsequent active specific immunotherapy: dendritic cell (DC) vaccines plus modulatory immunotherapy; and maintenance ICD therapy. There were no differences in the number of vaccines (median: 2), total number of DCs (median: 25.6 × 106), number of NDV injections (median: 31), and number of mEHT sessions (median: 28) between both groups. The median OS of 28 unmeth patients was 22 m (2y-OS: 39%), confirming previous results. OS of 22 meth patients was significantly better (p = 0.0414) with 38 m (2y-OS: 81%). There were no major treatment-related adverse reactions. The addition of IMI during/after standard of care should be prospectively explored.
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