Cambridge Healthtech Institute 第3回

Neoantigen Targeted Therapies

( 新抗原標的化療法 )

ゲノム時代の個別化がん免疫療法

2018年8月30日~31日

新抗原標的化療法をテーマにしたこのカンファレンスプログラムでは、製薬会社やバイオテクノロジー企業のオピニオンリーダー、主要な研究機関の開発チームで中心的な役割を担っている研究者、がん免疫療法を行っている臨床医などが一堂に会し、免疫系を利用してがんを治療する患者中心のアプローチの導入に関する研究やケーススタディを披露します。主なトピックは、NGSを利用した腫瘍特異性新抗原の同定、コンピューターを利用した免疫原性ネオエピトープの予測、個別化ワクチン、新たな抗体、併用療法によるネオエピトープの標的化などです。


Final Agenda

8月30日 (木)

7:45 am Registration & Morning Coffee

個別化がんワクチン

8:25 Chairperson's Opening Remarks

Nathaniel Wang, PhD, Head, Vaccines and Therapeutics, Viral Systems, Synthetic Genomics, Inc.


8:30 FEATURED PRESENTATION: Neoantigen-Based Vaccines for Breast Cancer

Keith Knutson, PhD, Director, Cancer Vaccine & Immune Therapies Program, Mayo Clinic

Breast cancer causes 500,000 deaths each year. Rather than continue to add to the costs of treatment, we should advance promising approaches for prevention such as vaccination. One approach for a breast cancer vaccine is to target aberrantly expressed 'self' antigens. To produce such a vaccine, we're aiming to achieve key milestones, namely identifying peptide epitopes from cancer antigens and identifying systems that induce durable T cell responses.

9:00 In situ Vaccination and the Power of Ignorance

Robert Pierce, MD, Scientific Director, Immunopathology Core, Fred Hutchinson Cancer Research Center

9:30 Development of a Rapid Personalized Self-Assembling Vaccine for Cancer

Mark C. Poznansky, MD, PhD, Director, Vaccine & Immunotherapy Center, Massachusetts General Hospital; Associate Professor, Harvard Medical School

We have developed a novel personalized self-assembling vaccine (SAV) for cancer that has the potential to be synthesized and delivered to the patient in 20 days. The vaccine consists of a fusion protein containing the broadly immune activating Mycobacterium tuberculosis derived heat shock protein 70 and avidin which self assembles with selected biotinylated immunogenic peptides derived from identified neoantigens. We have demonstrated proof of concept that SAV works in the context of generating T cell specific responses to infectious agents.

10:00 Coffee Break in the Exhibit Hall (Last Chance for Poster Viewing)

10:45 Vaccibody's Approach to Cost-Effective Personalized Cancer Neoantigen Vaccines Inducing a Unique CD8-Dominated T Cell Response

Agnete Fredriksen, PhD, President and CSO, Vaccibody AS

Vaccibody's technology potentiates vaccines by attracting, activating and delivering antigens to antigen presenting cells which generates a unique CD8-dominated T cell response. By administering the DNA vaccine format of the Vaccibody vaccine, a rapid, cost-effective and robust manufacturing process can be applied which lends itself perfectly to develop commercially viable patient-specific vaccines on demand. A clinical study using targeted Vaccibody neoepitope DNA vaccines in multiple advanced cancer indications is ongoing.

11:15 Agenus' Synthetic Neoantigen Vaccine Platforms, Including Novel Phosphopeptide Tumor Targets

Daniel Levey, PhD, Senior Director Vaccine Research, R&D, Agenus, Inc.

Agenus' vaccine platform of synthetic neoantigens complexed to recombinant heat shock protein 70 (HSC70) and administered along with QS-21 Stimulon® adjuvant elicits an antigen-specific immune response in both mice and humans. Leveraging our in silico Agenus Immunogenic Mutation (AIM™) workflow, we are able to generate an optimal immunogenic vaccine blueprint for our AutoSynVax™ vaccines, which are uniquely designed and manufactured for each patient based on NGS profiling of their tumor. Our PhosphoSynVax™ vaccine is an off-the-shelf vaccine targeting a novel class of tumor neoantigens arising from post translational modifications of self-peptides due to dysregulated cell signaling pathways in cancer. Using mass-spectrometry, we have identified a large library of cancer-specific phosphopeptide tumor targets (PTTs) recognized by TCRs. Given Agenus' diverse IO portfolio, we have the opportunity to combine our immune education strategies with immunomodulatory antibodies to increase therapeutic efficacy.

11:45 Development of Synthetic Self-Replicating RNA Platforms for Oncology Vaccines and Therapeutics

Nathaniel Wang, PhD, Head, Vaccines and Therapeutics, Viral Systems, Synthetic Genomics, Inc.

RNA as a vaccine and therapeutic modality has become a focus of significant interest. SGI has developed a self-amplifying RNA replicon that overcomes existing limitations and has shown improved protein expression, immunogenicity, and resistance to immune shutdown. This improved RNA replicon is also compatible with formulation technologies, which lower the effective dose required for immunization and improve cellular immunological memory. These engineered advantages enable novel applications of this platform for oncology vaccines and therapeutics.

12:15 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:45 Session Break

新抗原標的化療法

1:40 Chairperson's Remarks

Philip Arlen, MD, President & CEO, Precision Biologics


1:45 FEATURED PRESENTATION: T Cells against Tumor Neoantigens: How Many Are Likely Needed for Clinical Efficacy and Can Contemporary Vaccines Get Us There?

Andrew Allen, PhD, CEO & President, Gritstone Oncology

Two key challenges in neoantigen-directed therapeutics are: 1) accurate neoantigen identification from "sea" of tumor mutations (achieved with deep learning approach, trained on human tumors); 2) induction of large numbers of polyfunctional neoantigen-specific T cells. Novel vaccine approaches to problem (2), in combination with checkpoint modulators, can drive extremely high and sustained T cell responses in non-human primates. We can compare these to T cell numbers observed in successful adoptive cell therapy.

2:15 The Discovery and Development of Novel Monoclonal Antibodies Targeting Neoantigens

Philip Arlen, MD, President & CEO, Precision Biologics

Immunogenic neoantigens were derived from a membrane preparation of pooled allogeneic colorectal cancer. The membrane was separated into various fractions by molecular weight and screened for immunogenicity. An immunogenic fraction was identified and used as a vaccine in a clinical trial for patients with chemotherapy refractory disease. There was a correlation observed in patients who developed antibody responses to therapy with both antitumor responses as well as prolongation in overall survival. This vaccine was used as platform to screen monoclonal antibodies as potential therapeutic candidates.

2:45 Sponsored Presentation (Opportunity Available)

3:15 Refreshment Break

3:45 Induction of Potent Neoantigen Targeted CD8+ T Cell Responses via Optimized DNA-Based Immunotherapy

Niranjan Y. Sardesai, PhD, COO, Inovio Pharmaceuticals

Tumor neoantigen targeting for the development of patient specific immunotherapies has emerged as a viable approach for cancer immunotherapy. Considerable efforts are being directed towards the accurate identification and prediction of targetable neoantigens for each patient. However equally critical is the platform deployed for the administration of the selected neoantigens to generate patient T cell responses in vivo. We will discuss the use of optimized plasmid DNA based approach.

4:15 Advaxis' Lm Technology™

Robert G. Petit, PhD, Executive Vice President & CSO, Advaxis

4:45 Targeting Neoantigens without the Need to Identify Them: Update on the Phase 3 ADAPT Trial with Rocapuldencel-T in Advanced RCC

Charles A. Nicolette, PhD, CSO & Vice President, R&D, Argos Therapeutics, Inc.

Rocapuldencel-T is a dendritic cell-based immunotherapy where the dendritic cells are programmed with total amplified autologous tumor mRNA plus synthetic RNA encoding CD40 ligand. Clinical and immunologic data from the Phase 3 ADAPT trial in advanced RCC will be presented that is consistent with specific targeting of neoantigens.

5:15 End of Day

8月31日 (金)

8:00 am Breakout Discussion Groups with Continental Breakfast

This session features discussion groups that are led by a moderator who ensures focused conversations around the key issues listed. Attendees choose to join a specific group, and the small, informal setting facilitates sharing of ideas and active networking. Details on the topics and moderators are available on the conference website.

個別化された免疫療法のための新抗原の同定と選択

9:00 Chairperson's Remarks

Nathaniel Wang, PhD, Head, Vaccines and Therapeutics, Viral Systems, Synthetic Genomics, Inc.

9:05 An HLA-Agnostic Functional Neoantigen Discovery Platform for Personalized Cancer Vaccines

Stephen Schoenberger, PhD, Co-Director, San Diego Center for Precision Immunotherapy; Professor, La Jolla Institute for Allergy and Immunology

Accurate identification of patient-specific neoantigens (NeoAg) is essential to develop effective personalized cancer vaccines. We have developed WES/RNAseq-guided platform which combines a filtering algorithm based on sequencing metadata, rather than predicted HLA-binding, with in vitro functional T cell analysis. We report that >35% of selected expressed mutations can be verified as neoantigens in low mutational burden tumors by CD4+ and CD8+ T cells recognizing common activating mutations in driver oncogenes and numerous patient-specific "passenger" mutations.

9:35 Functional and Unbiased Neoantigen Calling as a Basis for Personalized Vaccines

Ezra Cohen, MD, Professor, Medicine, University of California, San Diego

Cancer presents a unique opportunity for the clinical application of precision immunotherapy due to the frequent expression of somatic mutations that can be recognized as tumor-specific neoantigens (NeoAgs) by a patient's T cells. Meaningful translation of this concept, however, has been hampered by the lack of reliable methods for identifying NeoAgs in cancers of low mutational burden and by the absence of suitable preclinical animal models for evaluating and optimizing the ability of NeoAg-specific T cells to recognize and eradicate autologous tumors. Through a collaborative effort within the San Diego Center for Precision Immunotherapy we have developed a set of novel bioinformatic and cellular tools which allows for the functional validation of NeoAg recognized by both CD4+ and CD8+ T cells at a higher rate than previously reported. This platform has allowed effective identification of NeoAg in solid tumors with low-to-moderate mutational burden through precision immunotherapy which is now being applied as a vaccine using synthetic long peptides.

10:05 Rapid High-Throughput Functional Selection of Neoantigens and Assessment of Their Safety

Dolores Schendel, CEO & CSO, Medigene

Neoantigens are an important class of highly specific target molecules for specific vaccine and TCR-based immunotherapies. Identification of neoantigens by next-generation sequencing and prediction of binding to the HLA allotypes of a patient, still leaves open the issue of actual immunogenicity and safety of neoantigen targets for therapeutic use. Medigene combines high throughput functional screening with sophisticated in silico tools to overcome several current limitations in selecting relevant neoantigens.

10:35 Coffee Break

11:00 Harnessing the Innate Immunogenicity of Foreign Viral Antigens to Fight Solid Tumors

David Anderson, PhD, CSO, Research & Development, VBI Vaccines, Inc.

CMV is expressed on over 95% of glioblastoma, medulloblastoma and breast cancers. Like neoantigens, it provides an opportunity to target a non-self antigen that has inherently higher immunogenicity than traditional tumor associated antigens. Recently CMV-specific autologous approaches have demonstrated over a 2X increase in overall survival in glioblastoma. VBI's approach utilizes its eVLP platform to restimulate CMV immunity by preferential uptake and presentation to dendritic cells. It offers an off-the-shelf approach to target CMV+ tumors.

11:30 Validation of Real Neoantigens with Mass Spectrometry

Harpreet Singh, PhD, President & CEO, Immatics US, Inc.

While neoantigens are a promising target class for immunotherapies in some patient populations, many researchers overlook that only a small fraction (presumably less than 1%) of all non-synonymous mutations are actually presented as pMHC targets and can thus act as neoantigens. Most strategies utilizing in silico prediction deliver more than 90% false-positive results. Such irrelevant antigens are currently often used in clinical trials and likely will not result in clinical benefit. Here, we show how Immatics' proprietary XPRESIDENT platform, an ultrahigh-sensitivity, high-throughput, high-fidelity mass spectrometry setup allows to validate real neoantigens. Furthermore, data from clinical applications of highly personalized applications is shown underlining the promise of tailored immunotherapies using both neoantigens and shared antigens.

12:00 pm A New Source of Highly Immunogenic Neoepitopes for Cancer Vaccines

Stephen Albert Johnston, PhD, Director, Center for Innovations in Medicine; Professor, School of Life Sciences, Biodesign Institute, Arizona State University; CEO, Calviri, Inc.

Mistranslation through microsatellites and mis-splicing produce 100x more neoantigens than DNA mutations. Frameshifts (FS) produced by mis-translation and splicing are highly immunogenic. These FS are protective in mouse models; humans and dogs with cancer raise immune responses to these FS, which can be detected using a rapid peptide array. In a mouse model this array-based system can be used to rapidly create a personal vaccine that shows protection.

12:30 Close of Neoantigen Targeted Therapies

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

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