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News Article | December 14, 2016
Site: www.businesswire.com

HELSINKI--(BUSINESS WIRE)--TILT Biotherapeutics Ltd, the oncolytic immunotherapy startup founded in 2013, has closed a financing round of 4.0M€ (~$4.3M) to progress its lead candidate, TILT-123, into Phase I clinical trials. This adds up to TILT’s seed funding, bringing its total funding to almost 10M€ (~$10.6M). TILT Biotherapeutics Ltd is a leading company globally working in the area of enabling tumor T-cell therapy with oncolytic viruses. The company’s patented technology involves utilization of oncolytic viruses for enhancement of tumor T-cell therapy. www.tiltbio.com Curative treatment for solid tumors - 90% of all cancers The lead candidate, TILT-123, is a preclinical stage TNFα/IL2 armed oncolytic adenovirus. GMP production is ongoing and the first phase I clinical trials are aimed to start early 2018. TILT-123 will be used to enhance tumor infiltrating lymphocyte (TIL), chimeric antigen receptor (CAR-T), and checkpoint inhibiting antibody therapy. One of the trials, for which the funding raised will be used, will take place in two centers in Europe and address metastatic melanoma in combination with TILT-123 and TILs. As stated by TILT’s founder/CEO Akseli Hemminki, “TILT-123 is the only oncolytic virus which has been specifically designed with T-cell therapies and checkpoint inhibitors in mind. Moreover, we have already seen in humans that the virus backbone is safe and is able to access distant metastases by the vascular route”. In addition to these unique features, TILT’s product has been engineered for improved efficacy and safety in cancer cells. Professor Hemminki and colleagues have published over 200 scientific papers and treated over 300 patients with different oncolytic viruses. Supported by Finnish investors and an EU grant TILT’s investors include Lifeline Ventures Ltd, the Finnish Funding Agency for Technology and Innovation (Tekes), the European Commission, and business angels. The latest funding round consists of loans from Tekes and important equity investments from Lifeline Ventures and private investors. "TILT is an interesting investment opportunity because the TILT technology is likely to be the most effective oncolytic immunotherapy in the context of T-cell therapies and anti-PD1, and the team has an unparalleled track record in clinical translation" says Timo Ahopelto, one of the founders of Lifeline Ventures. TILT is further aiming at expanding its current investor base to secure capital for additional Phase I/II clinical trials and establishing collaborations with companies having synergic technologies in the immuno-oncology field, notably those with checkpoint inhibitors or CAR-T.


Hemminki O.,University of Helsinki | Hemminki O.,Kotka Central Hospital | Hemminki A.,University of Helsinki | Hemminki A.,TILT Biotherapeutics Ltd
OncoImmunology | Year: 2016

Treating cancer patients with oncolytic viruses that activate the immune system to fight cancer is an increasingly appealing option. Potency of the approach seems promising while safety has been consistent. Biological correlative data indicates that combining oncolytic immunostimulatory viruses with other existing treatments is tempting and many trials are ongoing. © 2016 Taylor & Francis Group, LLC.


Liikanen I.,University of Helsinki | Koski A.,University of Helsinki | Merisalo-Soikkeli M.,University of Helsinki | Hemminki O.,University of Helsinki | And 6 more authors.
OncoImmunology | Year: 2015

With the emergence of effective immunotherapeutics, which nevertheless harbor the potential for toxicity and are expensive to use, biomarkers are urgently needed for identification of cancer patients who respond to treatment. In this clinical-epidemiological study of 202 cancer patients treated with oncolytic adenoviruses, we address the biomarker value of serum high-mobility group box 1 (HMGB1) protein. Overall survival and imaging responses were studied as primary endpoints and adjusted for confounding factors in two multivariate analyses (Cox and logistic regression). Mechanistic studies included assessment of circulating tumor-specific T-cells by ELISPOT, virus replication by quantitative PCR, and inflammatory cytokines by cytometric bead array. Patients with low HMGB1 baseline levels (below median concentration) showed significantly improved survival (p D 0.008, Log-Rank test) and radiological disease control rate (49.2% vs. 30.0%, p D 0.038, x2 test) as compared to high-baseline patients. In multivariate analyses, the low HMGB1 baseline status was a strong prognostic (HR 0.638, 95% CI 0.462–0.881) and the best predictive factor for disease control (OR 2.618, 95% CI 1.004–6.827). Indicative of an immune-mediated mechanism, antitumor T-cell activity in blood and response to immunogenic-transgene coding viruses associated with improved outcome only in HMGB1-low patients. Our results suggest that serum HMGB1 baseline is a useful prognostic and predictive biomarker for oncolytic immunotherapy with adenoviruses, setting the stage for prospective clinical studies. © Ilkka Liikanen, Anniina Koski, Maiju Merisalo-Soikkeli, Otto Hemminki, Minna Oksanen, Kalevi Kairemo, Timo Joensuu, Anna Kanerva, and Akseli Hemminki.


Tahtinen S.,University of Helsinki | Gronberg-Vaha-koskela S.,University of Helsinki | Lumen D.,University of Helsinki | Merisalo-Soikkeli M.,University of Helsinki | And 6 more authors.
Cancer Immunology Research | Year: 2015

Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immunogenic due to inherent pathogen-associated molecular patterns. Here, we studied the capacity of adenovirus to overcome resistance of chicken ovalbumin-expressing B16.OVA murine melanoma tumors to adoptive ovalbumin-specific CD8+ T-cell (OT-I) therapy. Following intraperitoneal transfer of polyclonally activated OT-I lymphocytes, control of tumor growth was superior in mice given intratumoral adenovirus compared with control mice, even in the absence of oncolytic virus replication. Preexisting antiviral immunity against serotype 5 did not hinder the therapeutic efficacy of the combination treatment. Intratumoral adenovirus injection was associated with an increase in proinflammatory cytokines, CD45+ leukocytes, CD8+ lymphocytes, and F4/80+ macrophages, suggesting enhanced tumor immunogenicity. The proinflammatory effects of adenovirus on the tumor microenvironment led to expression of costimulatory signals on CD11c+ antigen-presenting cells and subsequent activation of T cells, thus breaking the tumor-induced peripheral tolerance. An increased number of CD8+ T cells specific for endogenous tumor antigens TRP-2 and gp100 was detected in combination-treated mice, indicating epitope spreading. Moreover, the majority of virus/T-cell-treated mice rejected the challenge of parental B16. F10 tumors, suggesting that systemic antitumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer. © 2015 American Association for Cancer Research.


Hirvinen M.,University of Helsinki | Capasso C.,University of Helsinki | Guse K.,University of Helsinki | Garofalo M.,University of Helsinki | And 10 more authors.
Molecular Therapy - Oncolytics | Year: 2016

In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate-and eventually the long-lasting adaptive immunity against cancer.


Kanerva A.,University of Helsinki | Koski A.,University of Helsinki | Liikanen I.,University of Helsinki | Oksanen M.,University of Helsinki | And 8 more authors.
Molecular Therapy | Year: 2015

Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial, an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (from 170 to 208 days, P = 0.0012, N = 148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N = 90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N = 37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses. © 2015 The American Society of Gene & Cell Therapy.


Liikanen I.,University of Helsinki | Liikanen I.,University of California at San Diego | Tahtinen S.,University of Helsinki | Guse K.,University of Helsinki | And 7 more authors.
Molecular Cancer Therapeutics | Year: 2016

Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with fulllength trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus, Ad5/3-Δ24-tras, coding for human trastuzumab antibody heavy- and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-Δ24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-Δ24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-Δ24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-Δ24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. © 2016 American Association for Cancer Research.


Hemminki O.,University of Helsinki | Parviainen S.,University of Helsinki | Juhila J.,University of Helsinki | Turkki R.,Institute for Molecular Medicine Finland FIMM | And 16 more authors.
Oncotarget | Year: 2015

Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Δ24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site ("Δ24"). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor- and adenovirus-specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.


Koski A.,University of Helsinki | Bramante S.,University of Helsinki | Kipar A.,University of Helsinki | Kipar A.,University of Liverpool | And 9 more authors.
Molecular Therapy | Year: 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.


Hirvinen M.,University of Helsinki | Rajecki M.,University of Helsinki | Kapanen M.,Cancer Center | Parviainen S.,University of Helsinki | And 8 more authors.
Human Gene Therapy | Year: 2015

For long it has been recognized that tumor necrosis factor alpha (TNFa) has anticancer characteristics, and its use as a cancer therapeutic was proposed already in the 1980s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency, and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore, the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene-mediated direct effect such as TNFa-mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa-expressing adenovirus showed increased cancer-eradicating potency, which was shown to be because of elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24-hTNFa-treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and antitumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy. Copyright 2015, Mary Ann Liebert, Inc.

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