Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§

Signup to see this grant's details

Interaction of Immune System with Oncolytic Measles Virus Therapy of Medulloblastoma
Translational
Medulloblastoma, Childhood (Brain Cancer)
Lay Summary

Medulloblastoma (MB) is the most common malignant brain tumor in children. The Group 3 MB patients have the worst prognosis and dismal 5-year survival rate among the four distinct subtypes of MB: WNT, SHH, Group 3 and Group 4 tumors. Sadly, MB survivors face life-long debilitating neurocognitive side effects from craniospinal radiation that is a mainstay of the standard-of-care treatment protocols. Clearly, more effective alternate therapies with fewer side effects are needed. Oncolytic viruses (OVs) (Onco=tumor + lytic=killing) selectively replicate in and kill cancer cells and may attract immune cells into the tumor microenvironment to stimulate a systemic anti-tumor response. We have shown that oncolytic measles virus (MV) is preclinically effective against MB in immunodeficient mice, however, these models do not allow examination of the effect of immune system on MV therapy. To study the effect of immune system on MV therapy, we have developed the first immunocompetent MV-sensitive murine model of Group 3 MB (the CSCG model). MV infects and replicate in CSCG cells and intratumoral MV treatment of tumor-bearing mice significantly prolonged. In this proposal, we will study the interaction of immune system with MV therapy and the efficacy of combination of MV and immune-checkpoint blockade for the treatment of medulloblastoma. Activation of checkpoints on immune cells is known as a mechanism for tumor cells to evade host’s immune surveillance. Immunotherapy using inhibitors of the checkpoint signaling proteins such as the programmed death 1 receptor (PD-1) on T cells has shown clinical benefit in some adult cancers. In our model, a subset of mice were long-term survivors from MV treatment and remained tumor free for at least 150 days (considered “cured”). These mice were re-challenged with a 3-times greater number of tumor cells in the contralateral hemisphere than original injection, but tumor failed to grow for at least 150 additional days. This strongly suggests that MV induces anti-tumor immunity. We hypothesize that MV attracts immune cells into the tumor microenvironment and the combination of MV therapy with immune checkpoint inhibition will be synergistic to enhance the anti-tumor effect in MB tumors. We will use the cutting-edge technology of CyTOF (Mass Cytometry by Time of Flight) to examine tumor-infiltrating immune cells and their activation state in response to MV therapy. Under the Pacific Pediatric Neuro-Oncology Consortium (PNOC), we are currently conducting a phase 1 trial assessing the safety of intrathecal administration of MV in recurrent MB and AT/RT patients (NCT02962167), and preliminary results from the trial support a favorable safety profile of modified MV encoding the human thyroidal sodium iodide symporter (MV-NIS) given into the tumor bed or into the subarachnoid space. The results of the proposed study will inform the ongoing study and may be rapidly translated into clinic. In addition, the knowledge gained will guide future clinical trial designs for the treatment of other pediatric CNS tumors that combine MV therapy with immune checkpoint inhibition strategies.

Executive Summary

There is increasing evidence from preclinical and clinical studies that immune-based therapies may provide effective anti-tumor response against brain cancers including medulloblastoma (MB), the most common malignant tumor in children. Among the four molecularly distinct subtypes of MB, the Group 3 tumors are highly aggressive and frequently recur with metastatic spread causing increased rate of mortality. Sadly, standard therapy including craniospinal radiation is severely toxic to the developing brain of young children and causes life-long morbidity to survivors. Immunotherapy may provide effective and safer alternative for MB treatment. However, the tumor-associated immunosuppression and immune evasion strategies often render immune system tolerant to tumors. Oncolytic viruses have emerged as a new class of cancer-selective immunotherapeutics with proven clinical safety. We have demonstrated preclinical efficacy of oncolytic measles virus (MV) on MB tumors (local and CSF-disseminated) and are currently investigating this therapy for recurrent MB patients in an active phase 1 trial (NCT02962167). Because our immune system has naturally evolved to activate a response against viruses, it is logical to combine the immune-stimulating MV therapy with inhibitors of immune checkpoints such as the PD-1 receptor that works to inhibit activation of cytotoxic T cells. This combination has potential to act synergistically and unleash the systemic anti-tumor response. We propose to investigate MV therapy combined with PD-1 inhibition for the treatment of MB tumors, both local and CSF-disseminated, using our first-of-its-kind MV-permissive, immune-competent mouse model of Group 3 MB. This model forms tumor in the brain of syngeneic immune-competent mice, allows replication of MV and tumor cells are killed by MV in vivo significantly prolonging survival. A complete response was observed in 60% of treated mice and the remaining animals had significantly prolonged survival compared to the untreated cohort. Long-term survivors remained tumor-free for at least 150 days post treatment. These mice (n=3) were re-challenged with a 3-times greater number of tumor cells than the original injection in the contralateral hemisphere, but tumor failed to grow for at least additional 150 days post-injection. This suggests that MV induces systemic anti-tumor immunity. Using our model, we can investigate the details of interaction of the immune system with MV therapy. We will compare infiltration of immune cells in the tumor microenvironment in response to MV therapy by cutting-edge technology of CyTOF and will compare differential gene expression patterns by RNA sequencing of tumor. The effect of treatment on signaling will be studies by profiling Cytokines/Chemokines by antibody arrays into the cerebrospinal fluid (CSF) collected from mice in different treatment groups. Positive results from this study will have a significant impact to guide designs of future clinical trials for MB treatment. In our early phase clinical trial, MV therapy in children with recurrent medulloblastoma and AT/RT given intrathecally has shown a favorable safety profile to date, and we are encouraged that this work will provide the rationale for a combination approach with PD1 inhibition to enhance efficacy. In addition, the findings from the study will be easily applied to other types of tumors, both in children and adults, and lay a groundwork for future studies to assess combination of other oncolytic viruses with immune checkpoint blockade. We will be the first to investigate the safety and efficacy of intrathecal administration of anti-PD-1 treatments and the results may have a broad impact for many tumor types.

Description of Research Proposal

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Integer fermentum vestibulum lacinia. Duis id aliquam nibh, ut mattis leo. Nulla ac dui at sapien posuere facilisis ut quis ex. Aliquam vestibulum blandit tristique. Integer pretium dui ac nulla accumsan, et finibus velit euismod. Proin placerat, nunc eu sodales facilisis, tellus justo efficitur risus, non blandit diam nulla ac ligula. Aliquam ullamcorper quam leo, porttitor dictum ex tempor ac. Ut efficitur, justo et auctor volutpat, ex ex pulvinar est, sed consequat turpis leo nec ipsum. Nunc tempor, turpis ut ullamcorper tempor, dolor dui varius dui, et congue quam nisi vel nunc.

Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Donec faucibus, turpis sit amet maximus dapibus, sapien nisl bibendum turpis, pharetra commodo tellus libero vel nulla. Sed nec velit viverra, congue sapien et, gravida libero. Proin eget ante eget turpis egestas accumsan. Aliquam arcu nibh, aliquam rhoncus vulputate in, pellentesque at sem. Maecenas cursus tempus nibh id tempus. Mauris dolor sapien, lacinia sit amet condimentum at, dapibus eget lectus. Phasellus vel pellentesque ex. Nunc aliquam in ligula at tristique. In mollis suscipit felis eu finibus. Nullam non dignissim nibh, nec suscipit ex. Suspendisse tincidunt et mauris id finibus. Aliquam vehicula a sem quis venenatis.

Suspendisse leo odio, rutrum et viverra ut, consequat finibus enim. Vivamus dolor nisl, viverra eu egestas vel, blandit in nulla. Curabitur auctor purus non est volutpat bibendum. Proin fringilla magna sed metus maximus, in dictum neque suscipit. Sed ornare ut mi ut sodales. Nulla efficitur urna nunc, non molestie nunc egestas ut. Nunc arcu lorem, semper ut tincidunt ac, eleifend quis elit.

Sed at tortor et tortor tincidunt feugiat id in dui. Vivamus eget justo nisl. Aenean congue laoreet nisl a elementum. Nunc consectetur velit non ligula sollicitudin, quis eleifend urna sollicitudin. Sed tincidunt, nisl quis varius venenatis, dui massa condimentum tellus, sed sollicitudin diam magna mollis augue. Sed venenatis commodo purus id malesuada. Aenean volutpat elit vel gravida consectetur. Vestibulum diam quam, lacinia ac tortor eget, tincidunt dapibus dui. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Proin nisl leo, pretium sed arcu imperdiet, hendrerit sollicitudin sem. Duis non magna at nunc sagittis ullamcorper a id est. Maecenas cursus nisl in faucibus hendrerit.

Sed hendrerit vitae purus et tempor. Aenean vitae varius velit. Nullam aliquet ipsum elit. Mauris vestibulum purus et metus imperdiet, quis gravida eros pretium. Curabitur rutrum nunc vitae tincidunt condimentum. Aenean sit amet augue velit. Nunc tristique quis lorem id pharetra. Pellentesque sollicitudin, eros sed egestas rutrum, nulla nisl sodales elit, ut imperdiet nunc lectus sit amet nulla. Ut malesuada finibus libero. Curabitur mi dolor, sollicitudin quis bibendum quis, dictum sed enim.

Pellentesque nibh erat, egestas sit amet sagittis malesuada, rhoncus at neque. Mauris maximus commodo tortor, non egestas magna finibus vitae. Sed hendrerit nulla vel venenatis tempor. Suspendisse tristique tincidunt libero et placerat. Nam tincidunt condimentum lorem, vel pharetra est iaculis sed. Nullam ac tincidunt orci. Quisque pharetra ut sem sit amet aliquam. Phasellus risus libero, varius in condimentum vel, commodo id ipsum. Aliquam in metus cursus, mattis diam ut, aliquam magna. Suspendisse facilisis dui et orci varius, suscipit facilisis augue dapibus. In eget nibh ipsum. Suspendisse eget pharetra est, quis condimentum felis. Fusce scelerisque congue libero, sed aliquam mi elementum a. Etiam scelerisque ante non auctor porta. Nam eu nunc id ex finibus dictum. Praesent dui ex, dictum ac massa eget, rutrum gravida nisi.

Sed egestas arcu in dui euismod, eget faucibus massa iaculis. Etiam efficitur lectus et purus lobortis, ac blandit eros rutrum. Proin bibendum consectetur leo vel gravida. Etiam et ultricies sapien. Nam lacinia tellus erat, id facilisis est consequat et. Morbi quis risus in neque iaculis pharetra ut consectetur libero. Aenean feugiat tempor mi eu posuere.

Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.