Dendritic cell vaccine inoculation in parallel with chemotherapy

Abstract

To provide an optimum therapy schedule in combination with a standard chemotherapy in order to establish a dendritic cell (DC) vaccine as an effective therapy option to cancer.SOLUTION: The present invention relates to a dendritic cell vaccine to be used for cancer therapy in which a dendritic cell vaccine is administered to a patient in parallel with a chemotherapy using at least one kind of chemotherapeutic agent.SELECTED DRAWING: None

Description

[Background technology]

[0001] If harnessed well, the immune system is a powerful tool that can enhance the efficacy of cytotoxic drugs and improve outcomes for cancer patients. Vaccination is expected to be an effective method to eliminate cancer cells by harnessing the immune system. Most of the activity of vaccines is mediated by antigen-specific CD8 + T cell-dependent, antigen-specific CD8 + T cells give rise to cytotoxic T lymphocytes (CTLs), which then reject the cancer (Palucka and Banchereau 2013). Cytotoxic CD8 +A necessary immune system factor for T cell induction is antigen presentation by appropriate antigen-presenting cells (APCs). Dendritic cells (DCs) are the most efficient APCs and are a crucial component of vaccines due to their ability to capture, process and present antigens to T cells (Banchereau and Steinman 1998). Several vaccination strategies using DCs against various cancers have been developed (Galluzzi et al., 2012). One of them involves culturing patient-derived (autologous) monocytes in the presence of a specific combination of cytokines, loading the monocytes with tumor-associated antigens (TAA) ex vivo, maturing them into DCs in the presence of adjuvants and re-administering the resulting DCs to the patient. Another strategy involves the delivery of tumor-associated antigens to DCs in vivo or using exosomes derived from DCs (Galluzzi et al., 2012). These strategies have been tested against various cancers in multiple clinical trials (Galluzzi et al., 2012; Vacchelli et al., 2013; Bloy et al., 2014; Garg et al., 2017). However, these DC vaccines evaluated in clinical trials have shown relatively low therapeutic efficacy. Various reasons are related to the low therapeutic efficacy, such as due to the maturation factors used in the preparation of DC vaccines, insufficient immunogenicity of the tumor-associated antigens loaded on DCs, suboptimal in vivo localization of the administered DCs, and / or due to the formulation of the DC vaccines (Galluzzi et al., 2012). Furthermore, another reason for the low therapeutic efficacy is related to the design of clinical trials, where standard treatment is usually performed with chemotherapy. It has been shown that the recovery of the immune system after chemotherapy may be slower than previously thought (Verma et al., 2016), which highlights the unpredictability of the combination of DC vaccines and chemotherapy.

[0002] On the other hand, despite the great efforts to optimize the first-line treatment of tumors and create optimal therapeutic approaches to overcome recurrence after chemotherapy, there are still many tumor diseases that require advanced medical care, and there are few treatment options available to patients when the disease recurs. Most patients who experience recurrence eventually die. DC vaccines may be a novel treatment option for such tumor patients, and the side effects of DC vaccines are expected to be very mild compared to, for example, standard chemotherapy drugs, which may improve the life expectancy and quality of life of patients. However, the only DC vaccine approved so far, Sipuleucel T, has been able to show some additional benefit, but according to the German Institute for Quality and Efficiency in Health Care (IQWIQ), its effectiveness cannot be evaluated (press release “Sipuleucel-T in prostate cancer: indication of added benefit” of the IQWIQ, dated March 19, 2015; https: / / www.iqwig.de / en / press / press-releases / press-releases / sipuleucel-t-in-prostate-cancer-indication-of-added-benefit.6618.html; cited December 12, 2017), and the hope of a significant improvement for patients has not been delivered by the DC vaccine.

[0003] Besides aiming to optimize the DC vaccine manufacturing protocol, optimal treatment schedules in combination with standard chemotherapy are still needed to establish DC vaccine as an effective treatment option aiming to extend the disease-free interval until the next relapse or next line of treatment and / or improve patient survival. Summary of the Invention [Means for solving the problem]

[0004] The inventors have now surprisingly determined that administration of a DC vaccine in conjunction with chemotherapy is beneficial in extending overall survival and progression-free survival in cancer patients compared to standard treatment of chemotherapy alone. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] Definitions of terms: "Dendritic cell vaccine" or "DC vaccine" refers to human dendritic cells prepared without or with antigenic material that may be administered for therapeutic purposes. The dendritic cells are preferably prepared by loading the dendritic cells with tumor-associated peptides, whole antigens derived from DNA or RNA, whole antigenic proteins, idiotypic proteins, tumor lysates, whole tumor cells, or whole antigens delivered by viral vectors as antigens, and then optionally matured with a Toll-like receptor agonist. More preferably, the dendritic cells are loaded with whole tumor cells that have undergone immunogenic cell death, as described, for example, in Fucikova et al. (2014). Furthermore, such loaded dendritic cells may be further matured. The maturation of the dendritic cells is achieved, for example, by culturing the loaded dendritic cells in the presence of maturation factors, such as Toll-like receptor agonists (e.g., poly[I:C] or LPS).

[0006] "Toll-like receptor agonist" refers to a molecule that binds to Toll-like receptors (TLRs), such as lipopolysaccharides that bind to TLR4, and double-stranded RNA or polyinosinic acid:polycytidylic acid (poly[I:C]) that bind to TLR3. In addition, TLR1 agonists, TLR2 agonists, TLR5 agonists and TLR8 agonists are also suitable for maturation. The expression of TLRs in dendritic cells and their functions are reviewed by Schreibelt et al. (Schreibelt et al., 2010). See monocyte-derived dendritic cells (moDCs) listed in Table 1 of this document.

[0007] "Chemotherapy" is a treatment using drugs or agents that stop the growth of cancer cells, either by killing them (cytotoxic agents) or by stopping their division (cytostatic agents). Chemotherapy drugs can include alkylating or alkylating-like agents, such as carboplatin or cisplatin; antimetabolites, such as gemcitabine, pemetrexed, or methotrexate; antitumor antibiotics, such as doxorubicin; topoisomerase inhibitors, such as topotecan, irinotecan, or etoposide; and mitotic inhibitors, such as docetaxel, paclitaxel, vinblastine, or vinorelbine. Further examples of chemotherapy drugs are provided by the American Cancer Society and can be found at https: / / www.cancer.org / treatment / treatments-and-side-effects / treatment-types / chemotherapy / how-chemotherapy-drugs-work.html ("American Cancer Society - How Chemotherapy Drugs Work" 2016). Such chemotherapy drugs may typically be small molecule drugs (organic compounds with a low molecular weight (e.g., less than 900 daltons)). Chemotherapy may include other treatments such as hormones or hormone analogs, small molecule drugs (e.g., kinase inhibitors, PARP inhibitors), vaccines other than DC vaccines, biological agents (e.g., antibodies), or combinations thereof. Chemotherapy may be administered orally, by injection, infusion, or via the skin, depending on the type and stage of cancer being treated. Chemotherapy may be administered alone or in combination with other treatments, such as surgery or radiation therapy.

[0008] In the context of the present invention, in a preferred embodiment, "chemotherapy" excludes any agent used in cancer therapy that reduces regulatory T cell responses. Thus, in one embodiment of the present invention, the chemotherapeutic agent is not cyclophosphamide (Berd and Mastrangelo 1987; Fucikova et al., 2017).

[0009] The term "chemotherapy" also encompasses "neoadjuvant chemotherapy," which is a chemotherapy treatment given as a first step to shrink a tumor before the main treatment, usually surgery, is given.

[0010] The term "chemotherapy" also encompasses "adjuvant chemotherapy", which is a chemotherapy treatment administered after initial treatment (e.g. surgery or radiation therapy) for the treatment of residual tumors and / or for the prevention or treatment of metastases. In the context of the present invention, dendritic cell vaccines are not considered adjuvant chemotherapy.

[0011] Chemotherapy is usually administered in cycles, with a treatment period followed by a recovery period, followed by another treatment period, etc. Thus, a "cycle" refers to one treatment period followed by one recovery period.

[0012] More than one type of drug can be given as "combination chemotherapy" to treat the same disease.

[0013] Chemotherapy is "completed" when the last administration of chemotherapy agent is completed in the final cycle. For the avoidance of doubt, the final cycle may be the last scheduled cycle or may be the last administered cycle if chemotherapy is "discontinued" (e.g., discontinued prior to completion due to undesirable side effects or lack of response to treatment).

[0014] "Maintenance therapy" is therapy given after initial chemotherapy or started during initial chemotherapy after a complete or partial response has been achieved (Sakarya 2016;Ellis 2016). "Maintenance therapy" is given after the cancer has disappeared or regressed, to prevent the cancer from coming back. Maintenance therapy may include treatment with selected drugs with mild side effects, such as hormones and hormone analogs (e.g., enzalutamide, abiraterone, tamoxifen, LHRH agonists and LHRH antagonists), kinase inhibitors (e.g., erlotinib, afatinib, gefitinib, crizotinib, alectinib, ceritinib, dabrafenib, trametinib and osimertinib), PARP inhibitors (e.g., olaparib, niraparib), vaccines other than DC vaccines, or biological agents (e.g., antibodies such as bevacizumab, pembrolizumab, nivolumab). Thus, maintenance therapy aims to maintain the patient in complete or partial remission. Maintenance therapy is preferably performed for a long period of time without adverse events that would force the patient to discontinue treatment. Treatment with interferon / hydroxychloroquine (IFN / HCQ) is excluded from maintenance therapy. Preferably, the initial chemotherapy is an adjuvant chemotherapy followed by a maintenance therapy.

[0015] The administration of the DC vaccine may be started simultaneously with chemotherapy or during chemotherapy. Thus, the DC vaccine therapy is administered "concurrently" with chemotherapy. "Concurrent" administration includes the case where the DC vaccine therapy and chemotherapy are completed or stopped at the same time, or the case where the DC vaccine therapy is continued even after chemotherapy is completed or stopped. "Concurrent" administration also includes the case where the DC vaccine can be administered at any stage of ongoing chemotherapy, for example, during any cycle of ongoing chemotherapy. The DC vaccine may be administered during the treatment and / or recovery period of each cycle. Thus, "concurrent" administration of chemotherapy and DC vaccine means that chemotherapy overlaps with treatment with the DC vaccine at least for some time.

[0016] If chemotherapy is effective, the patient "responds" to the chemotherapy, ie, the tumor does not grow further and / or does not metastasize, or the tumor shrinks in size.

[0017] A patient is "refractory" to chemotherapy if the patient does not respond to the chemotherapy initially or during treatment, meaning that the cancer is resistant or has acquired resistance to the chemotherapy drug.

[0018] A treated cancer is considered to have "recurred" or "come back" if cancer or signs and symptoms of cancer return after a period of improvement.

[0019] A "biological agent" is a substance, often expressed by recombinant technology, used to prevent, diagnose, or treat cancer and other diseases. Biological agents include antibodies, nucleic acid-based drugs, fusion proteins, hormones, hormone analogs, or cytokines. Unlike most small molecule chemotherapeutic agents, which have defined structures and are often chemically synthesized, biological agents are often complex mixtures and / or post-translationally modified substances that are not easily identified or characterized. Biological agents include those produced by bioengineering techniques, but they tend to be heat sensitive and susceptible to microbial contamination. In a preferred embodiment of the invention, the biological agent is not a virus.

[0020] "Primary therapy" is the first treatment given to a disease. Primary therapy is often performed as part of standard treatment, for example, surgery followed by chemotherapy and radiation therapy. Primary therapy alone is usually the best accepted treatment for the disease. If the primary therapy does not cure the disease or causes severe side effects, another treatment option may be added or used instead of the primary therapy. Primary therapy is also called induction therapy, initial therapy or primary treatment.

[0021] "Primary chemotherapy" refers to a treatment with at least one chemotherapeutic agent administered as part of a primary therapy. "Primary chemotherapy" is understood to exclude the concurrent use of dendritic cell vaccine therapy.

[0022] "Second-line chemotherapy" is chemotherapy given when a patient does not respond to the initial treatment (first-line therapy) or when the first-line therapy is no longer effective. "Tertiary chemotherapy" is chemotherapy given when neither the initial treatment (first-line therapy) nor the subsequent treatment (second-line therapy) is effective or when both are no longer effective.

[0023] "Overall survival (OS)" is the length of time that a patient diagnosed with a disease (such as cancer) survives from the date of diagnosis, randomization, or start of treatment for the disease. In clinical trials, measuring overall survival is one way of measuring the effectiveness of new treatments.

[0024] "Randomization" in clinical trials is the method of randomly assigning subjects to separate groups for comparing different treatments or other therapeutic interventions. Randomization gives each participant an equal chance of being assigned to one of the groups.

[0025] "Overall survival" is the percentage of people in a study or treatment group who are alive for a given period of time after diagnosis of a disease (such as cancer), randomization, or the start of treatment for a disease. Overall survival is often expressed as the 5-year survival rate, which is the percentage of people in a study or treatment group who are alive 5 years after diagnosis or the start of treatment.

[0026] "Progression-free survival (PFS)" is the length of time a patient lives without their disease getting worse during or after treatment for a disease (such as cancer). Measuring progression-free survival in clinical trials is one way of finding out how well a new treatment is working.

[0027] If a patient is in complete remission and all signs and symptoms of cancer disappear, the patient is "cured" of cancer. In a preferred embodiment, if complete remission lasts for more than 5 years, the patient is considered to be "cured". Thus, for example, if the patient does not achieve complete remission, if the patient's disease recurs, or if the cancer is refractory, the patient is not "cured" of the disease by the treatment.

[0028] A "standard of care" (SOC) is a treatment that is accepted by the health care profession as appropriate for a particular type of disease and is widely used by health care professionals. Standards of care are also called best practice, standard of medical care, and standard of care.

[0029] "Serious Adverse Event (SEA)" refers to any serious, unwanted experience associated with the use of a medicinal product in a patient. A serious adverse event has occurred if the patient outcome is life-threatening, death, hospitalization / prolonged hospitalization, birth defect, persistent or significant disability / incapacity requiring preventive intervention for permanent disability / injury, or a serious medical event (e.g. serious problems with breathing, blood disorders, convulsions / seizures or drug dependency).

[0030] "Dose" refers to a measured, predetermined amount of drug or DC vaccine administered at a given time, for example, a daily dose of x cells.

[0031] "Tumor associated peptide" refers to a peptide that may be associated with a tumor. The presence of a tumor associated peptide may be highly correlated with the presence of a particular tumor cell. A tumor associated peptide may be highly specific for a particular tumor, but may also be associated with other types of tumors. Furthermore, a tumor associated peptide may be found in normal cells as well as tumor cells, but may be highly expressed in tumor cells. A tumor associated peptide may comprise only a partial sequence of a larger tumor associated protein, i.e., the "whole" tumor associated protein. A tumor associated peptide may be isolated from the corresponding tumor cell or may be produced as a recombinant peptide.

[0032] "Entire antigen derived from DNA or RNA" refers to DNA or RNA encoding the entire sequence of the antigen being loaded into dendritic cells.

[0033] By "whole antigen protein" is meant that the antigen comprises the full-length sequence of the protein of interest as an antigen, and not just peptide epitopes derived from the full-length protein.

[0034] "Idiotype protein" refers to an idiotypic target protein composed of antigenic determinants unique to the variable region of, for example, an immunoglobulin (Ig) clone expressed by a tumor cell.

[0035] "Tumor lysate" refers to a composition comprising tumor cells and a lysis buffer, the lysis buffer comprising an agent that lyses the tumor cells. Thus, intracellular, transmembrane and / or extracellular components of the tumor are contained in the tumor lysate and function as antigens according to the present invention.

[0036] "Whole tumor cells" refers to the use of intact tumor cells that have not been lysed with a lysis buffer.

[0037] "Whole antigen delivered by a viral vector" means that a viral vector is used to deliver an antigen to a dendritic cell. For example, the whole antigen can be a whole protein, which is encoded by the viral vector and expressed in the dendritic cell when the viral vector transfects the dendritic cell.

[0038] "Taxanes" refers to a class of compounds consisting of diterpenes with a taxadiene core structure. Examples of taxanes include, but are not limited to, paclitaxel, docetaxel, and cabazitaxel.

[0039] "Platinum complex" refers to a metal complex compound in which the metal moiety is platinum. Platinum is complexed, for example, with an oxygen atom or a nitrogen atom of one or more organic or inorganic compounds to form a platinum complex. Examples of platinum complexes include, but are not limited to, carboplatin and cisplatin.

[0040] As used herein, a "newly diagnosed cancer," such as a "newly diagnosed ovarian cancer," means that the cancer patient has not previously been diagnosed with that particular cancer (e.g., ovarian cancer).

[0041] As used herein, "advanced ovarian cancer" refers to ovarian cancer stage IIIB, IIIC, or IV according to the International Federation of Gynecology and Obstetrics [FIGO] staging classification.

[0042] In the detailed description and claims of the present invention, when the term "comprising" is used, it does not exclude other elements. For the purposes of achieving the present invention, aspects described using the term "consisting of" are considered to be preferred embodiments over aspects described using the term "comprising". In the following, when a particular group is defined as comprising at least a certain number of embodiments, it is understood that a group consisting of only these embodiments is also disclosed, which is preferred.

[0043] Where an indefinite or definite article such as "a", "an" or "the" is used to refer to a singular noun, this also includes the plural of the noun in question, unless specifically stated otherwise.

[0044] "At least one" in expressions such as "at least one chemotherapeutic agent" means one or more chemotherapeutic agents. In the same context, "a combination thereof" refers to a combination comprising two or more chemotherapeutic agents.

[0045] Technical terms are used in their ordinary sense. If a particular term denotes a particular meaning, the definition of that term is set forth below in the context in which the term is used.

[0046] Detailed Description of the Invention In a first aspect, the present invention relates to a dendritic cell vaccine (DC vaccine) for use in the treatment of cancer, characterized in that the dendritic cell vaccine is administered to a patient in parallel with chemotherapy using at least one chemotherapeutic agent. The chemotherapeutic agent or agents used may be determined by a competent physician and may be part of the standard of care recommended for the cancer to be treated. Depending on the standard of care, the chemotherapeutic agent or agents may be administered in one or more cycles. The duration of each cycle of chemotherapy, the frequency of cycles and the number of cycles depend on the cancer to be treated and the chemotherapeutic agent or agents used. The chemotherapeutic agent or agents may be administered in full on a particular day of a cycle, over several consecutive days or continuously, on an outpatient or inpatient basis. Treatment may continue for a few minutes, hours or days, depending on the specific protocol. Chemotherapy may be repeated weekly, every two weeks or monthly. Usually, a cycle is defined monthly. For example, a cycle may consist of two biweekly chemotherapy sessions followed by a recovery period. In most cases, the total number of cycles, or the time from the start to the end of chemotherapy, is determined by clinical studies and trials. As long as signs of cancer are detectable, the duration of chemotherapy treatment is determined by the cancer's response to chemotherapy. If the cancer disappears completely (complete response), chemotherapy may be continued for one or two more cycles after this disappearance is observed, thus maximizing the chances of eradicating all microscopic or undetectable tumor. If the cancer regresses but does not disappear (partial response), chemotherapy may be continued as long as it can be tolerated and the cancer does not grow (progress).

[0047] If the cancer continues to grow during chemotherapy, chemotherapy is stopped, the patient is considered refractory to chemotherapy, and chemotherapy is considered complete. Chemotherapy is also considered complete if the last dose of chemotherapy is completed in the last cycle.

[0048] Surprisingly, we found that cancer patients who received the DC vaccine in parallel with chemotherapy had a longer overall survival than those treated with chemotherapy alone (see Figures 2, 3, 5, 6, and 8). Even more surprising, we observed an increase in overall survival when the DC vaccine was added to different types of chemotherapy combinations (carboplatin / paclitaxel or carboplatin / gemcitabine), when the DC vaccine was used in different treatment settings (in combination with first-line or second-line chemotherapy), and when the DC vaccine was used to treat different types of cancer (e.g., ovarian or lung cancer).

[0049] The DC vaccine may be formulated for intravenous, intradermal or subcutaneous administration, preferably subcutaneous. The DC vaccine may be formulated, for example, for infusion or bolus injection, and may be administered with an adjuvant (Elster, Krishnadas and Lucas 2016). Administration may be systemic, locoregional or local. When a single dose is injected, it may be administered in one or multiple injections, but is preferably administered in two separate injections. The DC vaccine may be administered to the patient subcutaneously, preferably to a lymph node region adjacent to the area in which the cancer to be treated originates. Various delivery systems are known and may be used to deliver the DC vaccine. The method of administration may be left to the discretion of the physician.

[0050] In the context of the present invention, "chemotherapy" is understood to refer to a class of compounds used as cytostatic or cytotoxic agents. In a preferred embodiment, the at least one chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, pegylated liposomal doxorubicin, etoposide, topotecan, irinotecan, olaparib, rucaparib, trabectedin, niraparib, mitoxantrone, cabazitaxel, vinorelbine, pemetrexed, vinblastine and albumin-bound paclitaxel. The specific regimen of chemotherapy may follow the established standard of care for the particular cancer to be treated or may be at the discretion of the physician. In a preferred embodiment, the chemotherapeutic agent is not cyclophosphamide. More specifically, the chemotherapeutic agent according to the present invention is not low-dose cyclophosphamide. Low doses of cyclophosphamide are used to suppress the function of regulatory T cells (Berd and Mastrangelo 1987; Fucikova et al., 2017) and have been used in the prior art prior to dendritic cell vaccination (Dong et al., 2016). Chemotherapy may include drugs prescribed as maintenance therapy or until cancer progression, such as hormone therapy (e.g., enzalutamide, abiraterone, tamoxifen, LHRH agonists and LHRH antagonists), targeted therapy (e.g., erlotinib, afatinib, gefitinib, crizotinib, alectinib, ceritinib, dabrafenib, trametinib and osimertinib), and biological agents (e.g., antibodies such as bevacizumab, pembrolizumab, nivolumab, etc.). For the avoidance of doubt, chemotherapy within the meaning of this invention does not include agents prescribed to treat co-morbidities, to avoid or treat side effects, or to assist the patient in recovering from side effects (e.g., erythropoietin).

[0051] The first administration of DC vaccine is administered in parallel with each chemotherapy cycle, and may be further administered after chemotherapy is completed / stopped.The first administration of DC vaccine may start from the first chemotherapy cycle, from the second chemotherapy cycle, from the third chemotherapy cycle, or from any subsequent chemotherapy cycle.In particular, the first administration of DC vaccine starts after the second chemotherapy cycle is completed, and continues to be administered after chemotherapy is completed / stopped.In a preferred embodiment, at least six chemotherapy cycles are administered to the patient.

[0052] In a preferred embodiment, the DC vaccine is administered to the patient in parallel with chemotherapy using at least one chemotherapeutic agent, and this chemotherapy is the first-line chemotherapy. The type of first-line chemotherapy depends on the cancer to be treated and its stage (e.g., TNM staging system-tumor / node / metastasis (National Cancer Institute-Diagnosis and Staging, 2015) or FIGO staging of ovarian cancer (FIGO Staging of Ovarian Cancer, 2014)). For example, in the case of first-line treatment of ovarian cancer, the dendritic cell vaccine can be administered in parallel with combination chemotherapy of taxanes and platinum complexes, in particular combination chemotherapy of paclitaxel and carboplatin or combination chemotherapy of docetaxel and carboplatin. Alternatively, the combination of chemotherapeutic agents can be a combination of pegylated liposomal doxorubicin and carboplatin. More commonly, first-line chemotherapy treatments used for various stages of cancer (e.g., ovarian, prostate, lung cancer) that may be administered with dendritic cell vaccines are listed at http: / / www.cancertherapyadvisor.com (CancerTherapyAdvisor 2017b, 2017c, 2017a).

[0053] Furthermore, the present invention relates to DC vaccine therapy that is administered to patients with cancer that has not been cured by previous chemotherapy treatment in parallel with chemotherapy.The reason why the patient's cancer has not been cured by previous chemotherapy can be that the patient's cancer recurs after the completion or discontinuation of previous chemotherapy, or that the patient's cancer is refractory to previous chemotherapy.The DC vaccine is preferably first administered during the second or subsequent chemotherapy, starting after the end of the second cycle of chemotherapy, and continues to be administered after the completion / discontinuation of chemotherapy.

[0054] In another aspect, the DC vaccine of the present invention used for the treatment of cancer may continue to be administered in combination with maintenance therapy after the completion of initial chemotherapy.Examples of maintenance therapy for ovarian cancer include treatment with bevacizumab (continuation maintenance therapy after first-line treatment with carboplatin and paclitaxel), treatment with olaparib (after second-line and third-line treatment for platinum-sensitive cancer) or treatment with niraparib (after third-line treatment).Examples of maintenance therapy for non-small cell lung adenocarcinoma include treatment with bevacizumab after first-line treatment.In a preferred embodiment, maintenance therapy includes maintenance therapy with bevacizumab, olaparib and / or niraparib.

[0055] Various types of DC vaccines are well known in the art and can be classified into various types according to the method of loading and pulsing DCs with tumor antigens (Turnis and Rooney 2010; Elster, Krishnadas and Lucas 2016), which are incorporated herein by reference. Thus, the DC vaccine of the present invention used for treating cancer by administering to patients in parallel with chemotherapy is a DC vaccine loaded with antigenic material ex vivo, and the antigenic material is preferably selected from tumor-associated peptides, whole antigens derived from DNA or RNA, whole antigenic proteins, idiotypic proteins, tumor lysates, whole tumor cells, and whole antigens delivered by viral vectors. The DC vaccine of the present invention may be optionally matured with Toll-like receptor (TLR) agonists (e.g., poly[I:C] or LPS). In particular, the DC vaccine of the present invention is matured with poly[I:C], a TLR3 agonist. The tumor lysate may be an autologous tumor lysate, an allogeneic tumor lysate, or a xenogeneic tumor lysate. Similarly, the whole tumor cells may be an autologous tumor cell, an allogeneic tumor cell, or a xenogeneic tumor cell. The whole tumor cells and tumor lysate may be derived from one or more tumor cell lines and may be selected based on the presence of a particular antigen that matches the tumor of the patient to be treated. The antigenic material may be selected and loaded onto DCs by techniques known to those skilled in the art (Turnis and Rooney 2010; Elster, Krishnadas and Lucas 2016).

[0056] In a preferred embodiment of the present invention, the antigenic material is whole tumor cells, preferably killed by high hydrostatic pressure (HHP), for example as described in WO2013 / 004708 and WO2015 / 097037, which are incorporated herein by reference (see Examples 1-4 of WO2013 / 004708 and Examples 2 and 3 of WO2015 / 097037). Briefly, whole tumor cells from cell lines or patients are treated with high hydrostatic pressure of 200-300 MPa for 10 minutes to 2 hours. Such treatment induces apoptosis in tumor cells, called immunogenic cell death (ICD). ICD is characterized by the expression of immunogenic molecules such as HSP70, HSP90, and calreticulin on the cell surface, and the release of HMGB1 and ATP, which are markers of late apoptosis. Thus, induction of ICD increases the uptake of tumor cells by dendritic cells, resulting in dendritic cells that are loaded with and present a variety of tumor antigens. Apoptosis-induced tumor cells may be cryopreserved prior to loading into dendritic cells.

[0057] In a preferred embodiment, the whole tumor cells loaded in the DC vaccine are allogeneic with the patient. Although autologous tumor cells are said to be better matched with the tumor antigens of the patient, in reality, it requires a very complicated process to manufacture DC vaccine from autologous tumor biopsy samples. Therefore, it is preferable to use allogeneic tumor cells (e.g., tumor cell lines) that express tumor antigens that overlap with the tumor antigens normally expressed in the tumor disease to be treated.

[0058] For this reason, dendritic cells may be derived from autologous monocytes of the patient to be treated. As used herein, "monocytes" refer to circulating white blood cells characterized by a bean-shaped nucleus and the absence of granules. Dendritic cells can be differentiated from monocytes. Monocytes can be isolated from the patient's blood using techniques known to those skilled in the art, preferably using leukopheresis. By using leukopheresis, autologous monocytes can be collected from the patient to be treated, and the collected autologous monocytes can be used for the preparation of DC vaccines. Leukopheresis may be performed using techniques known to those skilled in the art.

[0059] Typically, dendritic cells are derived from monocytes harvested by leukapheresis before chemotherapy, and chemotherapy is administered in combination with dendritic cell vaccination. Because many chemotherapy regimens induce neutropenia, leukapheresis performed after chemotherapy initiation may harvest fewer viable cells, thus reducing the quantity and / or quality of the DC vaccine.

[0060] In another aspect of the present invention, the dendritic cell vaccine is administered to the patient 5 to 30 times, and in particular, the dendritic cell vaccine is administered to the patient 8 to 15 times. In another preferred embodiment, the dendritic cell vaccine is administered to the patient at least 8 times. In the manufacturing process of the dendritic cell (DC) vaccine, the DC vaccine may be divided into multiple portions, and in this case, each divided amount of the DC vaccine contains the same number of dendritic cells. Each divided amount of the DC vaccine can be frozen and stored until use. One or more divided amounts may constitute a single dose. The number of times that the DC vaccine is administered may be left to the discretion of the treating physician. The number of times that the DC vaccine is administered to the patient may be determined depending on whether or not the DC vaccine is administered during the maintenance treatment period. In addition, the number of times that can be administered during treatment may be determined depending on the yield of the leukoreduction method, but is preferably not less than 15 times. The DC vaccine may be administered to the patient in parallel with chemotherapy, with each administration being spaced apart every week, every two weeks, every three weeks, every five weeks, or every six weeks, preferably every three weeks. The administration interval may be determined according to the cancer to be treated, the stage of the cancer, or the schedule of chemotherapy cycles, or may be left to the discretion of the physician. The administration interval may also be changed during treatment, and the first administration may be performed at short intervals (e.g., every 3 weeks), and the subsequent administration may be performed at longer intervals (e.g., every 6 weeks). In a preferred embodiment, the first 5 administrations during chemotherapy treatment are performed every 3 weeks, and thereafter, the administration is preferably performed every 6 weeks for 5 administrations. This administration regimen is particularly preferred for the treatment of ovarian cancer and lung cancer.

[0061] In another preferred embodiment, the dendritic cell vaccine is administered in a dosing schedule comprising 5 doses every 3 weeks, followed by up to 10 doses every 6 weeks.

[0062] In one embodiment, the cancer to be treated is not a liquid tumor cancer such as leukemia or lymphoma, etc. Thus, the cancer is preferably a solid tumor cancer.

[0063] In another embodiment, the present invention relates to the treatment of cancer with DC vaccine administered to a patient in parallel with chemotherapy, wherein the cancer is selected from the group consisting of ovarian cancer, prostate cancer, lung cancer, brain cancer, leukemia and malignant melanoma.In a preferred embodiment, the cancer is selected from the group consisting of ovarian cancer, lung cancer, brain cancer and leukemia.

[0064] In another embodiment, the present invention relates to the treatment of cancer with a DC vaccine administered to a patient in parallel with chemotherapy, the cancer being selected from the group consisting of ovarian cancer, prostate cancer, lung cancer, brain tumors and malignant melanoma. Ovarian cancer includes epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer, and may be any of stages I to IV according to the International Federation of Gynecology and Obstetrics (FIGO) classification. Prostate cancer includes acinar adenocarcinoma, ductal adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma and small cell carcinoma, and may be classified using the Gleason score system. Lung cancer is particularly non-small cell lung cancer, including lung adenocarcinoma, squamous cell lung carcinoma and large cell lung carcinoma. In a preferred embodiment, the cancer to be treated is selected from the group consisting of ovarian cancer, prostate cancer, brain tumors and malignant melanoma.

[0065] In another preferred embodiment, the cancer to be treated is ovarian cancer, preferably newly diagnosed epithelial ovarian cancer or recurrent platinum-sensitive epithelial ovarian cancer, more preferably newly diagnosed epithelial ovarian cancer. In another particularly preferred embodiment, the cancer is recurrent advanced ovarian cancer or recurrent platinum-sensitive epithelial ovarian cancer.

[0066] In another preferred embodiment, the ovarian cancer is advanced ovarian cancer, newly diagnosed ovarian epithelial cancer or recurrent ovarian cancer.

[0067] In another preferred embodiment, the cancer to be treated is lung cancer, preferably non-small cell lung cancer, more preferably stage IV non-small cell lung cancer.

[0068] In a preferred embodiment, the at least one chemotherapeutic agent is selected from the group consisting of carboplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, pegylated liposomal doxorubicin, etoposide, topotecan, irinotecan, olaparib, rucaparib, trabectedin, niraparib, enzalutamide, abiraterone, mitoxantrone, cabazitaxel, vinorelbine, pemetrexed, methotrexate, vinblastine, albumin-bound paclitaxel, erlotinib, afatinib, gefitinib, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, osimertinib, biologic agents, and combinations thereof.

[0069] In another preferred embodiment, the chemotherapeutic agent is selected from the group consisting of carboplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, pegylated liposomal doxorubicin, etoposide, topotecan, irinotecan, trabectedin, mitoxantrone, cabazitaxel, vinorelbine, pemetrexed, methotrexate, vinblastine, albumin-bound paclitaxel, and combinations thereof.

[0070] In a preferred embodiment, the chemotherapy treatment further comprises a combination therapy of at least two chemotherapy agents.In one embodiment, the chemotherapy comprises a combination therapy selected from the following combinations: taxanes and platinum complexes, gemcitabine and platinum complexes, cisplatin and vinorelbine, cisplatin and etoposide, cisplatin and pemetrexed, cisplatin and irinotecan, gemcitabine and docetaxel, carboplatin and etoposide, carboplatin and pemetrexed, and gemcitabine and docetaxel. It is particularly preferred that the combination therapy is selected from the combination of paclitaxel and carboplatin, the combination of paclitaxel and cisplatin, the combination of docetaxel and carboplatin, the combination of cisplatin and vinorelbine, the combination of cisplatin and etoposide, the combination of cisplatin and gemcitabine, the combination of cisplatin and pemetrexed, the combination of cisplatin and irinotecan, the combination of gemcitabine and docetaxel, the combination of carboplatin and etoposide, the combination of carboplatin and gemcitabine, the combination of carboplatin and pemetrexed, and the combination of gemcitabine and docetaxel. The combination therapy may be according to the established standard of care or guidelines of the academic society for the particular cancer to be treated, or according to the doctor's judgment. In a preferred setting, preferably for the treatment of ovarian or lung cancer, preferably in the first line setting, the DC vaccine may be administered in parallel with chemotherapy using a combination of taxanes and platinum complexes, in particular with chemotherapy using paclitaxel and carboplatin.In another preferred setting, particularly for the treatment of recurrent advanced ovarian cancer, the DC vaccine may be administered in parallel with chemotherapy using a combination of platinum complexes and gemcitabine, preferably with chemotherapy using cisplatin and gemcitabine or with chemotherapy using carboplatin and gemcitabine.

[0071] In another preferred embodiment, the cancer is not lung cancer. In another preferred embodiment, the cancer is not stage III non-small cell lung cancer.

[0072] In a preferred embodiment, the chemotherapy treatment for stage IV non-small cell lung cancer is a platinum compound in combination with a taxane.

[0073] In another particularly preferred embodiment, the chemotherapy treatment for stage IV non-small cell lung cancer is carboplatin in combination with paclitaxel.

[0074] In another preferred embodiment, the chemotherapy treatment for newly diagnosed epithelial ovarian cancer is a platinum compound in combination with a taxane.

[0075] In another particularly preferred embodiment, the chemotherapy treatment for newly diagnosed epithelial ovarian cancer is carboplatin in combination with paclitaxel.

[0076] In another preferred embodiment, the chemotherapy treatment for recurrent platinum-sensitive epithelial ovarian cancer is a platinum-based compound in combination with gemcitabine.

[0077] In another particularly preferred embodiment, the chemotherapy treatment for recurrent platinum-sensitive epithelial ovarian cancer is carboplatin in combination with gemcitabine.

[0078] In yet another embodiment, leukapheresis is performed before administering the first cycle of chemotherapy to patients with first recurrent ovarian cancer. Autologous monocytes collected by leukapheresis are cultured in the presence of cytokines to obtain immature dendritic cells. The cytokines are preferably GM-CSF and IL-4. The immature dendritic cells are then loaded with tumor cells that have undergone immunogenic cell death, preferably an allogeneic tumor cell line derived from the same type of tumor as the tumor to be treated, which have been treated with high hydrostatic pressure. The dendritic cells are then further matured with a TLR agonist, preferably poly[I:C], to obtain a dendritic cell (DC) vaccine. The obtained DC vaccine has a concentration of approximately 1×10 per dose. 7The second line chemotherapy may be platinum (carboplatin or cisplatin) in combination with paclitaxel, gemcitabine or pegylated liposomal doxorubicin. The platinum and paclitaxel combination or platinum and gemcitabine combination is administered in 21 day cycles, and the platinum and pegylated liposomal doxorubicin combination is administered in 28 day cycles.

[0079] In one embodiment, the patient may be administered 4-6 cycles of chemotherapy, and the administration of the DC vaccine may begin simultaneously with the first administration of the second cycle of the chemotherapy. For example, in the case of a 21-day cycle, the administration of the DC vaccine may begin at the beginning of the third week of the second cycle after the administration of chemotherapy, or in the case of a 28-day cycle, the administration of the DC vaccine may begin at the beginning of the fourth week of the second cycle after the administration of chemotherapy. In one embodiment, the DC vaccine is administered once in all subsequent chemotherapy cycles. Once all chemotherapy cycles are completed, the DC vaccine may be administered up to seven additional times as a maintenance therapy. In a preferred embodiment, the DC vaccine is administered every six weeks as a maintenance therapy. In addition to the chemotherapy and DC vaccine treatment, the patient may be administered another established maintenance therapy, such as treatment with bevacizumab or a PARP inhibitor.

[0080] In another embodiment, a patient with stage IV non-small cell lung cancer (NSCLC) is subjected to leukapheresis prior to administration of the first cycle of chemotherapy. Autologous monocytes collected by leukapheresis are cultured in the presence of cytokines to obtain immature dendritic cells, preferably GM-CSF and IL-4. The immature dendritic cells are then loaded with tumor cells that have undergone immunogenic cell death, preferably an allogeneic NSCLC tumor cell line, treated with high hydrostatic pressure. The dendritic cells are then further matured with a TLR agonist, preferably poly[I:C], to obtain a dendritic cell (DC) vaccine. The obtained DC vaccine is administered at a concentration of approximately 1×10 per dose. 7The cells may be divided and stored in unit doses containing dendritic cells.

[0081] In one embodiment, the patient is administered 4-6 cycles of 3-week chemotherapy (e.g., a combination of carboplatin and paclitaxel). The first administration of the DC vaccine may occur during the second cycle of chemotherapy. For example, the first administration of the DC vaccine may occur at the beginning of the third week of the second cycle. In one embodiment, the DC vaccine is administered during all subsequent chemotherapy cycles. Once all chemotherapy cycles are completed, the DC vaccine may be administered up to 11 additional times as maintenance therapy. In a preferred embodiment, the DC vaccine is administered every 6 weeks as maintenance therapy.

[0082] The present invention is further described in the following sections. 1. A dendritic cell vaccine for use in the treatment of cancer, comprising administering the dendritic cell vaccine to a patient in parallel with chemotherapy using at least one chemotherapeutic agent. 2. The dendritic cell vaccine of item 1, wherein the first administration of the dendritic cell vaccine is administered during the chemotherapy, and optionally, the dendritic cell vaccine is further administered after the chemotherapy is completed. 3. The dendritic cell vaccine according to item 1 or 2, wherein the chemotherapy is a first-line chemotherapy. 4. The dendritic cell vaccine according to item 1 or 2, wherein the patient's cancer has not been cured by previous chemotherapy treatment. 5. The dendritic cell vaccine according to any one of items 1 to 4, which is further administered in combination with a maintenance therapy after completion of the chemotherapy. 6. The dendritic cell vaccine according to any one of items 1 to 5, wherein the dendritic cell vaccine is loaded with antigenic material ex vivo, the antigenic material being preferably selected from tumor associated peptides, whole antigens derived from DNA or RNA, whole antigenic proteins, idiotype proteins, tumor lysates, whole tumors, and whole antigens delivered by viral vectors. 7. The dendritic cell vaccine according to paragraph 6, wherein the antigenic material is whole tumor cells, preferably tumor cells killed by high hydrostatic pressure. 8. The dendritic cell vaccine of clause 6 or 7, wherein the whole tumor cells are allogeneic to the patient. 9. The dendritic cell vaccine according to any one of items 1 to 8, wherein the dendritic cells are derived from monocytes obtained by leukopheresis before chemotherapy. 10.i. administering the dendritic cell vaccine 5-30 times, in particular administering the dendritic cell vaccine 8-15 times; ii. administering the dendritic cell vaccine every week, every two weeks, every three weeks, every five weeks, or every six weeks; and / or iii. the dosing schedule includes five doses administered every three weeks, followed by five doses administered every six weeks during said chemotherapy; Item 10. The dendritic cell vaccine according to any one of Items 1 to 9, 11. The dendritic cell vaccine according to any one of items 1 to 9 and 10, wherein in i or ii, the dosing schedule comprises administering 5 doses every 3 weeks, followed by administering up to 10 doses every 6 weeks. 12. The cancer is selected from the group consisting of ovarian cancer, prostate cancer, lung cancer, brain cancer, leukemia and malignant melanoma; i. the cancer is preferably ovarian cancer, more preferably advanced ovarian cancer, newly diagnosed ovarian epithelial cancer or recurrent ovarian cancer; or ii. The cancer is preferably lung cancer, more preferably non-small cell lung cancer, even more preferably stage IV non-small cell lung cancer; Item 12. The dendritic cell vaccine according to any one of Items 1 to 11. 13. The dendritic cell vaccine according to any one of items 1 to 12, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, pegylated liposomal doxorubicin, etoposide, topotecan, irinotecan, olaparib, rucaparib, trabectedin, niraparib, enzalutamide, abiraterone, mitoxantrone, cabazitaxel, vinorelbine, pemetrexed, methotrexate, vinblastine, albumin-bound paclitaxel, erlotinib, afatinib, gefitinib, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, osimertinib, biological agents, and combinations thereof. 14. The chemotherapy comprises a combination therapy selected from a combination of taxanes and a platinum complex, a combination of gemcitabine and a platinum complex, a combination of cisplatin and vinorelbine, a combination of cisplatin and etoposide, a combination of cisplatin and pemetrexed, a combination of cisplatin and irinotecan, a combination of gemcitabine and docetaxel, a combination of carboplatin and etoposide, a combination of carboplatin and pemetrexed, and a combination of gemcitabine and docetaxel; especially, i. the chemotherapy comprises a combination of taxanes and platinum complexes, preferably selected from the combination of paclitaxel and carboplatin, the combination of paclitaxel and cisplatin, and the combination of docetaxel and carboplatin, more particularly, the combination is paclitaxel and carboplatin, or ii. The combination is gemcitabine and a platinum complex, in particular cisplatin and gemcitabine, or carboplatin and gemcitabine; Item 14. The dendritic cell vaccine according to any one of Items 1 to 13. [Brief description of the drawings]

[0083] [Figure 1]Schematic diagram of a clinical study in newly diagnosed ovarian cancer patients. Dendritic cell (DC) vaccine treatment administered in parallel with chemotherapy was compared to standard treatment using chemotherapy. "DCVAC OvCa" refers to a dendritic cell vaccine composed of dendritic cells loaded with ovarian cancer cells that have undergone immunogenic cell death and matured with Toll-like receptor ligands. Treatment period 1 corresponds to the chemotherapy period that also includes DC vaccine administration to treatment group A. Treatment period 2 corresponds to the period during which DC vaccine was continuously administered to treatment group A after completion of chemotherapy. [Diagram 2] Interim analysis of overall survival (OS) in the ITT population with newly diagnosed ovarian cancer in a clinical study. "Standard treatment" refers to chemotherapy alone. [Diagram 3] Figure 1 shows an interim analysis of overall survival (OS) in the PP population with newly diagnosed ovarian cancer in a clinical study. "Standard treatment" refers to treatment with chemotherapy alone. [Figure 4] Schematic diagram of a clinical study in patients with first relapsed ovarian cancer. DC vaccine treatment administered in parallel with chemotherapy was compared with standard treatment using chemotherapy. "DCVAC OvCa" refers to a dendritic cell vaccine composed of dendritic cells loaded with ovarian cancer cells that have undergone immunogenic cell death and matured with Toll-like receptor ligands. "Day 1 / 8 regimen" means that gemcitabine is administered on days 1 and 8 of each cycle, and carboplatin is administered on day 1 of each cycle. The length of each cycle is 21 days. [Diagram 5] Interim (A) and final (B) analyses of overall survival in the ITT population with first recurrent ovarian cancer in a clinical trial. "Standard treatment" refers to chemotherapy alone. [Figure 6] Interim (A) and final (B) analyses of overall survival in the PP population with first recurrent ovarian cancer in a clinical trial. "Standard treatment" refers to chemotherapy alone. [Figure 7]Schematic diagram of a clinical study for stage IV non-small cell lung cancer. DC vaccine treatment administered in parallel with chemotherapy was compared with standard chemotherapy. "DCVAC LuCa" refers to a dendritic cell vaccine composed of dendritic cells loaded with lung cancer cells that have undergone immunogenic cell death and matured with Toll-like receptor ligands. "Treatment period" refers to the total treatment time, including the period during which chemotherapy and DC vaccine are administered in combination and the period during which DC vaccine is administered alone after chemotherapy is completed. "Short cycle of 3 weeks" corresponds to a chemotherapy cycle that includes starting administration of DC vaccine from the second cycle of chemotherapy. "Long cycle of 11 cycles" corresponds to the period during which DC vaccine is administered alone after chemotherapy is completed. [Figure 8] This shows an interim analysis of overall survival (OS) in the PP population with stage IV non-small cell lung cancer in a clinical study. [Figure 9] Interim analysis of progression-free survival (PFS) of PP population with stage IV non-small cell lung cancer in clinical studies is shown. "Censored" in Figures 2, 3, 5, 6, 8 and 9 means that the patients were included in the clinical study by the time of reporting. Censored subjects are shown as whiskers on the Kaplan-Meier curves, and these subjects were discontinued during the observation interval. [Figure 10] This shows the administration schedule of DCVAC OvCa in a chemotherapy regimen. The ideal situation is shown in which the chemotherapy cycle is strictly 21 or 28 days. If the cycle is not 21 or 28 days, the next cycle of DCVAC OvCa is calculated based on the date of the last visit, and the patient is asked to visit the hospital to administer DCVAC in this cycle. "IMP" indicates the investigational drug, which is DCVAC OvCa in this case. The arrows indicate the ideal administration date, and the dotted arrows indicate ±3 days. EXAMPLES

[0084] Example 1. Dendritic cell (DC) vaccine The DC vaccine consisted of autologous dendritic cells loaded ex vivo with killed ovarian cancer cells and matured with Toll-like receptor 3 (TLR-3) ligands. The dendritic cells were derived from autologous monocytes harvested by leukapheresis. Monocytes isolated from the leukapheresis preparation were cultured in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 to obtain immature dendritic cells. The immature dendritic cells were loaded with cells of the ovarian cancer cell lines OV-90 and SK-OV-3 (at a 2:1 ratio). OV-90 and SK-OV-3 cells were treated with high hydrostatic pressure (HHP) (as described in Examples 1-4 of WO2013 / 004708) to induce immunogenic cell death before being added to the dendritic cell cultures (Fucikova et al., 2014). Tumor cell-loaded dendritic cells were matured with the TLR-3 ligand polyinosinic:polycytidylic acid (poly[I:C]).

[0085] The final preparation was cryopreserved in 1 mL of CryoStor CS10 cryopreservation medium supplemented with 10% dimethyl sulfoxide at approximately 1 × 10 cells / vial. 7 The cells were divided into unit doses each containing dendritic cells and stored frozen.

[0086] The DC vaccine was stored in aliquots and transported to the laboratory on dry ice at a temperature below -50°C. A single dose of the DC vaccine was then thawed and diluted with saline to a final volume of 5 mL. The diluted DC vaccine was administered subcutaneously to patients at two sites in the groin and contralateral side (2.5 mL for each administration site).

[0087] Example 2. Systematic standard therapy in patients with newly diagnosed ovarian cancer Guidelines on treatment options for newly diagnosed patients with ovarian cancer have been established by the European Society for Medical Oncology (ESMO) ( Ledermann et al., 2013 ). TIFF2025020203000001.tif170159

[0088] Surgery followed by first-line chemotherapy with platinum-based chemotherapy agents is the standard of care for the majority of patients and improves their progression-free survival (PFS) and overall survival (OS). However, despite initial responses, approximately 70% of patients will experience progressive disease recurrence and death within 5 years (Ledermann et al., 2013).

[0089] Example 3. Standard treatment for platinum-sensitive ovarian cancer at first recurrence Guidelines for therapeutic options for the treatment of platinum-sensitive ovarian cancer at first recurrence have been established by the European Society for Medical Oncology (ESMO) (Ledermann et al., 2013), which includes the recently approved addition of maintenance therapy. Second-line therapy: Taxanes in combination with platinum doublets appear to be beneficial, and other drug combinations, including gemcitabine, trabectedin, and pegylated liposomal doxorubicin, are also being evaluated in clinical trials. Agents should be selected based on toxicity profile and convenience of administration. · Targeted therapy: Bevacizumab in combination with carboplatin and gemcitabine is approved and recommended for platinum-sensitive recurrent disease in patients not previously treated with bevacizumab. Maintenance treatment after second-line chemotherapy: Olaparib, a PARP inhibitor, is indicated as a single agent for the maintenance treatment of adult patients with BRCA-mutated (germline and / or somatic) platinum-sensitive recurrent high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer who have responded (complete or partial response) to platinum-based chemotherapy. Niraparib, another PRAP inhibitor, is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who have responded (complete or partial response) to platinum-based chemotherapy.

[0090] Despite significant efforts in developing optimal therapeutic approaches aimed at overcoming relapse after chemotherapy, the available treatment options remain limited for patients with recurrent disease, and the majority of such patients ultimately die. Patients with recurrent disease are in dire need of new treatment options (such as DC vaccines) that could improve their life expectancy and quality of life.

[0091] Example 4. Clinical Data of Patients Newly Diagnosed with Advanced Ovarian Cancer This open-label, multicenter, phase II clinical trial was conducted to evaluate the efficacy and safety of DC vaccine administered in parallel with standard-of-care chemotherapy, carboplatin plus paclitaxel, compared with chemotherapy alone in women with newly diagnosed epithelial ovarian cancer who had undergone cytoreductive surgery.

[0092] A total of 65 patients were assigned to each treatment group in a 1:1 ratio by central randomization. A (34 patients) DC vaccine will be administered in parallel with standard treatment with chemotherapy. B (31 patients) receive standard chemotherapy treatment alone.

[0093] The DC vaccine was administered subcutaneously (SC) up to 10 times to patients in treatment group A. Six cycles of chemotherapy were planned in both treatment groups (Figure 1).

[0094] The intent-to-treat (ITT) population included all randomized patients, regardless of whether they received treatment or not, whereas patients randomized to arm A were required to receive at least one dose of DC vaccine to be included in the ITT population (ITT: arm A (concurrent administration of DC vaccine) consisting of 31 patients and arm B (standard care) consisting of 31 patients).

[0095] The per-protocol (PP) population included all randomized patients who received at least three cycles of standard treatment with chemotherapy and, for arm A, at least eight doses of DC vaccine, adhered to the inclusion criteria, and did not significantly deviate from the study protocol (PP: arm A (concurrent administration of DC vaccine) consisting of 29 patients and arm B (standard treatment) consisting of 30 patients).

[0096] The two treatment groups were matched with respect to demographic and disease characteristics (Table 1). Exposure to chemotherapy and DC vaccine is summarized in Table 2.

[0097] [Table 1]

[0098] [Table 2]

[0099] Results were calculated from the time of first treatment or randomization as the start of the clinical trial period. According to the original plan, two interim analyses of progression-free survival (PFS) and overall survival (OS) were performed in the per protocol population. The first was performed 6 months after the last dose of standard chemotherapy in the last enrolled patient, and the second was performed 12 months after. The results obtained from the two analyses were consistent. In the second interim analysis, 17 disease progressions were reported in treatment group A (PFS data maturity: 27.42%), and 13 patients died (OS data maturity: 20.97% calculated from the start of treatment and 19.35% calculated from the time of randomization). The results obtained from the second interim analysis are shown below. At the time of the second interim analysis, the median follow-up period of patients was 22.9 months (686 days) from the start of treatment and 22.8 months (694 days) from the time of randomization.

[0100] Efficacy in the ITT population Treatment group A (concurrent administration of DC vaccine) showed a clear trend towards improved overall survival compared to treatment group B (standard of care) (hazard ratio (HR) = 0.64, p = 0.4513 from treatment initiation, p = 0.4460 from randomization; Figure 2). Although this did not reach significance, this is likely due to the relatively small size of this clinical study. Concurrent treatment group A had significantly fewer deaths at 2 years than treatment group B using standard of care (see Figure 2).

[0101] Efficacy in PP population The same trend was observed in the PP population, i.e., treatment group A (concurrent administration of DC vaccine) showed a clear trend towards improved overall survival after 2 years compared to treatment group B (standard treatment) (HR = 0.51, p = 0.2777 from the start of treatment, p = 0.2735 from the time of randomization; Figure 3). Although it did not reach significance, this is likely due to the relatively small size of this clinical study. There were clearly fewer deaths in the concurrent treatment group A than in treatment group B using standard treatment (see Figure 3).

[0102] Thus, the data from the PP population support the findings from the ITT population suggesting a greater benefit from concurrent DC vaccine treatment compared with standard chemotherapy.

[0103] Overall, these clinical data surprisingly showed a benefit in patients randomized to receive DC vaccine in parallel with first-line chemotherapy (group A) when compared with standard treatment alone (group B). Even more surprisingly, it was found that delivering DC vaccine to patients multiple times (especially at least 8 times) was beneficial for patients. This can be estimated from the fact that the hazard ratio (HR) was lower in the PP population than in the ITT population (the selection criteria for the PP population were at least 8 doses of DC vaccine and 3 cycles of standard treatment with chemotherapy).

[0104] Patient characteristics were balanced between treatment arms A and B (see Tables 1 and 2). Thus, the benefit observed in treatment arm A compared with treatment arm B was not influenced by patient characteristics between these groups.

[0105] DC vaccine safety data In treatment group A, 14 serious adverse events were reported in 8 patients before the start of DC vaccine treatment, and 14 serious adverse events were reported in 9 patients after the start of DC vaccine treatment. In treatment group B, 14 serious adverse events were reported in 9 patients, although the reporting period was shorter than in the other groups. The most frequently reported serious adverse events were neutropenia, anemia, thrombocytopenia, ascites, and infected lymphocele.

[0106] These safety data indicate that the DC vaccine (including leukapheresis) was well tolerated and there were no safety issues associated with administration of the DC vaccine. No potential risks were detected or identified in this clinical trial.

[0107] Example 5. Clinical data of first recurrent ovarian cancer Clinical Data This clinical study was a randomized, open-label, parallel-group, multicenter, phase II clinical trial to evaluate the effect of adding DC vaccine to standard chemotherapy (combination of carboplatin and gemcitabine) in women with recurrent platinum-sensitive epithelial ovarian cancer. The aim of this clinical study was to explore the efficacy and safety of DC vaccine administered as add-on therapy in parallel with standard chemotherapy (combination of carboplatin and gemcitabine) compared with chemotherapy alone. An interim analysis was performed first, followed by a final analysis.

[0108] A total of 71 patients were assigned to treatment groups A and B in a 1:1 ratio by central randomization. Treatment group A (39 patients) received the DC vaccine in parallel with chemotherapy standard treatment, and treatment group B (32 patients) received chemotherapy standard treatment alone. The DC vaccine was administered up to 10 times to patients in treatment group A. In both treatment groups, each patient was scheduled to complete a total of 6, 8, or 10 cycles of chemotherapy standard treatment, according to the investigator's discretion (Figure 4).

[0109] The intent-to-treat (ITT) population included all randomized patients, regardless of whether they received treatment or not, whereas patients randomized to arm A were required to receive at least one dose of DC vaccine to be included in the ITT population (32 patients in arm A (concurrent administration of DC vaccine) and 32 patients in arm B (standard care)).

[0110] The per-protocol (PP) population included all randomized patients who received at least three cycles of standard treatment with chemotherapy and, for arm A, at least eight doses of DC vaccine, complied with the inclusion criteria, and did not significantly deviate from the study protocol (31 patients in arm A (concurrent administration of DC vaccine) and 27 patients in arm B (standard treatment)).

[0111] The two treatment groups were balanced with respect to patient demographics and cancer treatment history (Table 3). Exposure to chemotherapy and DC vaccine is summarized in Table 4.

[0112] [Table 3]

[0113] [Table 4]

[0114] Overall survival analysis The difference in overall survival, which was improved in arm A, approached statistical significance in the ITT population (HR=0.620, p=0.1565, interim analysis shown in Table 5, Figure 5A; HR=0.38, p=0.0032, final analysis shown in Table 5, Figure 5B) and in the PP population (HR=0.521, p=0.0662, interim analysis shown in Table 5, Figure 6A; HR=0.38, p=0.0032, final analysis shown in Table 5, Figure 6B). This represents a 38% reduction in risk of death in the ITT population and a 47.9% reduction in risk of death in the PP population compared to standard of care. Although statistical significance was not achieved, this is likely due to the relatively small size of the clinical study.

[0115] [Table 5]

[0116] Summary of efficacy data obtained from this clinical study (interim analysis) Results during the overall survival analysis approached statistical significance, indicating a significant positive impact on patient survival when DC vaccine was administered in parallel with standard second-line chemotherapy. The expected survival benefit was assessed from the extrapolated median survival data. This analysis showed that the expected survival benefit when treated with DC vaccine added in parallel with standard chemotherapy was 12.9 months for patients in the ITT population and 13.6 months for patients in the PP population.

[0117] Summary of efficacy data obtained from this clinical study (final analysis) The final analysis of overall survival was statistically significant and showed a significant positive impact on patient survival when DC vaccine was administered in parallel with standard second-line chemotherapy. The survival benefit was evaluated using median survival data. This analysis showed that the survival benefit of treatment with DC vaccine added in parallel with standard chemotherapy was 13.4 months for patients in the ITT population and 13.4 months for patients in the PP population.

[0118] Example 6. Benefits of DC vaccine over existing medical treatment for first recurrent ovarian cancer Currently, platinum combination chemotherapy is the treatment of choice for patients with platinum-sensitive ovarian cancer, but the combination of platinum-based chemotherapy agents should be selected based on toxicity profile and convenience of administration. In addition, bevacizumab in combination with carboplatin and gemcitabine has been approved and is recommended for platinum-sensitive recurrent disease in patients not previously treated with bevacizumab.

[0119] Surprisingly, this clinical study showed a survival benefit in patients who received DC vaccine in combination with carboplatin and gemcitabine compared with patients who received carboplatin and gemcitabine alone, which was greater than the survival benefit achieved by approved therapies of bevacizumab added to carboplatin and gemcitabine or bevacizumab added to carboplatin and paclitaxel (DC vaccine + carboplatin and gemcitabine, ITT population: HR = 0.620, p = 0.1565; bevacizumab + carboplatin and gemcitabine: HR = 0.952, p = 0.6479; bevacizumab + carboplatin and paclitaxel: HR = 0.823, p = 0.0447; Table 6). This represents a 38% reduction in the risk of death in patients treated with DC vaccine in combination with carboplatin and gemcitabine, compared with patients treated with carboplatin and gemcitabine alone.

[0120] [Table 6] TIFF2025020203000008.tif239149

[0121] Example 7. Clinical data for stage IV (metastatic) non-small cell lung cancer Clinical Data An open-label, multicenter, phase II clinical trial was evaluated in patients with stage IV (metastatic) non-small cell lung cancer (NSCLC). The clinical study aimed to compare the efficacy of DCVAC / LuCa plus chemotherapy (carboplatin and paclitaxel) with the efficacy of carboplatin and paclitaxel combination therapy alone in patients with stage IV NSCLC by measuring overall survival (OS) and progression-free survival (PFS). Progression-free survival was measured based on radiotherapy evaluation according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) (Eisenhauer et al., 2009).

[0122] A total of 62 patients were assigned to each treatment group in a 1:1 ratio by central randomization. A (33 patients) DC vaccine will be administered in parallel with standard treatment with chemotherapy. B (29 patients) receive standard chemotherapy treatment alone.

[0123] The DC vaccine was administered subcutaneously (SC) up to 15 times to patients in treatment group A. In both treatment groups, chemotherapy was scheduled for 4 to 6 cycles (Figure 7).

[0124] Patients who failed to produce DC vaccine and those who failed to comply with the study protocol were excluded from the per protocol (PP) population. In addition, patients randomized to arm A were required to receive at least one dose of DC vaccine to be included in the PP population.

[0125] The two treatment groups were matched with regard to demographic and disease characteristics.

[0126] Summary of efficacy data obtained from this clinical study The results of this clinical study showed that patients had improved overall survival (OS) when the DC vaccine was administered in parallel with standard second-line chemotherapy, as the Kaplan-Meier predicted overall survival up to the time of analysis showed a positive trend in the group receiving the DC vaccine in parallel with chemotherapy treatment (see Figure 8). Furthermore, the analysis showed that while all patients treated with chemotherapy alone eventually progressed to lung cancer disease, five patients (corresponding to 20% of the PP population) treated with the DC vaccine in parallel with chemotherapy did not show cancer progression (see Figure 9).

[0127] Example 8. Clinical trial to evaluate treatment of patients with first recurrent ovarian cancer using DCVAC / OvCa The clinical trial was designed as follows: At the start of treatment, patients with first recurrent ovarian cancer were randomized in a 2:1 ratio to DCVAC / OvCa + second-line chemotherapy or second-line chemotherapy alone (control group). All patients underwent leukapheresis before the administration of the first cycle of chemotherapy. Autologous monocytes collected by leukapheresis were cultured in the presence of GM-CSF and IL-4 to obtain immature dendritic cells according to Truxova et al. (Truxova et al., 2014). Ovarian cancer tumor cells from two cell lines, SK-OV-3 (obtained from Memorial Sloan-Kettering Cancer Center) and OV-90 (obtained from VAL-CHUM), were treated with high hydrostatic pressure (HHP) to induce immunogenic cell death (ICD) according to Example 1 described herein and Examples 1-4 of WO2013 / 004708, and the tumor cells were loaded onto immature dendritic cells overnight and further matured with the TLR agonist poly[I:C] to obtain DCVAC / OvCa. Matured dendritic cells were collected at approximately 1×10 per dose. 7The cells were divided into 21000 dendritic cells each, placed in a cryopreservation solution, and frozen. Secondary chemotherapy was platinum (carboplatin or cisplatin) in combination with paclitaxel, gemcitabine, or pegylated liposomal doxorubicin. The combination of platinum and paclitaxel or platinum and gemcitabine was administered in 21-day cycles, and the combination of platinum and pegylated liposomal doxorubicin was administered in 28-day cycles, both in accordance with the Marketing Authorization Directive. The patient was administered 4-6 cycles of chemotherapy, and the DC vaccine was administered starting from the second cycle of the chemotherapy. For the 21-day cycle, the chemotherapy was administered at the beginning of the third week of the second cycle of chemotherapy, followed by the first administration of the DC vaccine, or for the 28-day cycle, the chemotherapy was administered at the beginning of the fourth week of the second cycle of chemotherapy, followed by the DC vaccine (see FIG. 10). From this point on, the DC vaccine was administered in all chemotherapy cycles. After completing all chemotherapy cycles, DC vaccine will be administered every 6 weeks for up to 7 more doses as maintenance therapy. The control group will receive a placebo instead of DCVAC / OvCa. In addition to chemotherapy and DC vaccine treatment, other maintenance therapy may be administered to treated patients. This maintenance therapy will be performed with bevacizumab or PARP inhibitors.

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Claims

1. A dendritic cell vaccine for use in the treatment of cancer, comprising administering the dendritic cell vaccine to a patient in conjunction with chemotherapy using at least one chemotherapeutic agent.

2. The dendritic cell vaccine of claim 1 , wherein the cancer is selected from the group consisting of ovarian cancer, prostate cancer, lung cancer, brain cancer and leukemia.

3. The dendritic cell vaccine of claim 1 or 2, wherein an initial administration of the dendritic cell vaccine is administered during the chemotherapy, and optionally, a further administration of the dendritic cell vaccine is administered after completion of the chemotherapy.

4. The dendritic cell vaccine according to any one of claims 1 to 3, wherein the chemotherapy is a first-line chemotherapy.

5. The dendritic cell vaccine according to any one of claims 1 to 3, wherein the patient's cancer has not been cured by previous chemotherapy treatment.

6. The dendritic cell vaccine according to any one of claims 1 to 5, further administered in combination with a maintenance therapy after completion of said chemotherapy.

7. The dendritic cell vaccine of any one of claims 1 to 6, wherein the dendritic cell vaccine is loaded ex vivo with antigenic material, preferably selected from tumor associated peptides, whole antigens derived from DNA or RNA, whole antigenic proteins, idiotype proteins, tumor lysates, whole tumors, and whole antigens delivered by viral vectors.

8. The dendritic cell vaccine of claim 7, wherein the antigenic material is whole tumor cells, preferably tumor cells killed by high hydrostatic pressure.

9. The dendritic cell vaccine of claim 7 or 8, wherein the whole tumor cells are allogeneic to the patient.

10. The dendritic cell vaccine according to any one of claims 1 to 9, wherein the dendritic cells are derived from monocytes obtained by leukapheresis before chemotherapy.

11. i. administering the dendritic cell vaccine 5 to 30 times, in particular administering the dendritic cell vaccine 8 to 15 times; ii. administering the dendritic cell vaccine every week, every two weeks, every three weeks, every five weeks, or every six weeks; and / or iii. the dosing schedule includes five doses administered every three weeks, followed by five doses administered every six weeks during said chemotherapy; The dendritic cell vaccine according to any one of claims 1 to 10,

12. The dendritic cell vaccine of any one of claims 1 to 10 and 11, wherein in i or ii, the dosing schedule comprises 5 administrations every 3 weeks, followed by up to 10 administrations every 6 weeks.

13. i. the cancer is preferably ovarian cancer, more preferably advanced ovarian cancer, newly diagnosed ovarian epithelial cancer or recurrent ovarian cancer; or ii. The cancer is preferably lung cancer, more preferably non-small cell lung cancer, even more preferably stage IV non-small cell lung cancer; The dendritic cell vaccine according to any one of claims 1 to 12.

14. 14. The dendritic cell vaccine of any one of claims 1 to 13, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, paclitaxel, docetaxel, gemcitabine, pegylated liposomal doxorubicin, etoposide, topotecan, irinotecan, olaparib, rucaparib, trabectedin, niraparib, enzalutamide, abiraterone, mitoxantrone, cabazitaxel, vinorelbine, pemetrexed, methotrexate, vinblastine, albumin-bound paclitaxel, erlotinib, afatinib, gefitinib, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, osimertinib, biologic agents, and combinations thereof.

15. the chemotherapy comprises a combination therapy selected from a combination of a taxane and a platinum complex, a combination of gemcitabine and a platinum complex, a combination of cisplatin and vinorelbine, a combination of cisplatin and etoposide, a combination of cisplatin and pemetrexed, a combination of cisplatin and irinotecan, a combination of gemcitabine and docetaxel, a combination of carboplatin and etoposide, a combination of carboplatin and pemetrexed, and a combination of gemcitabine and docetaxel; especially, i. the chemotherapy comprises a combination of taxanes and platinum complexes, preferably selected from the combination of paclitaxel and carboplatin, the combination of paclitaxel and cisplatin, and the combination of docetaxel and carboplatin, more particularly, the combination is paclitaxel and carboplatin, or ii. The combination is gemcitabine and a platinum complex, in particular cisplatin and gemcitabine, or carboplatin and gemcitabine; The dendritic cell vaccine according to any one of claims 1 to 14.

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