The Vector

Volume 9, Issue 9: September 2020


Editorial Team

Edith Pfister, Ph.D. – Editor, The Vector
Karen Bulaklak, Ph.D. – Associate Editor, The Vector

Inside This Issue

Leadership Message
Breaking Through
Society News
Career Center
Public Policy
Industry News

Leadership Message


Register for Free for Next Week's COVID-19 Symposium

Hello everyone,

As summer comes to an end and we move into a new season, I hope you’re all looking forward to everything that ASGCT has planned for this month.

If you haven’t registered yet for our complimentary COVID-19 Symposium coming up Sept. 15-16, there is still time to do so. During the Symposium, we’ll hear from a variety of experts who will help us understand the origins, structure, and targets of SARS-CoV-2, the immune responses to infection, and information about treatment and vaccine strategies. In addition to invited speakers, we’ll hear presentations on the second day from researchers who have submitted abstracts to ASGCT. Abstracts will cover brand new research relating to COVID-19 on diagnostics, vaccine strategies, and gene and cell therapies. I’m very excited to hear from our speakers and from more than two dozen abstract presenters, and I highly encourage you all to attend.

Coming up right on the heels of the Symposium will be the 2020 Policy Summit, which you can still register for as well. I hope you can join us virtually for the three-day event where we’ll discuss regulatory, legislative, access, and ethical issues in the field. This year we’ll also have a couple of new panel discussion topics. One panel will focus on newborn screening policies and how they affect access to gene therapy, and the other will highlight policy implications of gene therapy for sickle cell disease from different viewpoints. Make sure you register so you don’t miss this event!

Lastly, I want to congratulate the ASGCT Patient Outreach Committee and the advocacy groups, stakeholders, and ASGCT staff they have worked with on the launch of a brand new Patient Education site. Along with the new site, the Patient Education Program will release new resources on diseases, vectors, clinical trials, and more. You can explore the new resources at PatientEducation.ASGCT.org.

I look forward to seeing you virtually very soon.

Stephen J. Russell, M.D., Ph.D.
ASGCT President

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Breaking Through


A Functional Screening Strategy for Engineering Chimeric Antigen Receptors with Reduced On-Target, Off-Tumor Activation

Di Roberto R, Castellanos-Rueda R, Frey S, Egli D, Vazquez-Lombardi R, Kapetanovic E, Kucharczyk J, Reddy S

DOI: https://doi.org/10.1016/j.ymthe.2020.08.003

Summary by Karen Bulaklak, Ph.D.

As cell-based therapies solidify their place in the arsenal for treating disease, the need for higher throughput screening strategies increases. Similar to selection of optimal small molecule drugs, a fine balance must be struck between safety and efficacy, which may be further complicated by the complexities of a cell-based product and its mechanism of action. A prominent example of this dilemma is chimeric antigen receptor (CAR) T-cell cancer immunotherapies, which harbor a transmembrane CAR that is composed of an external antigen-binding domain and an internal signaling domain. While two CAR T therapies that target CD19 overexpressed on malignant B cells have been approved and have led to remarkable improvements in patients, other cancers have been more challenging to treat. One issue is the potential for destruction of non-tumor cells that express low levels of tumor-associated antigens, which poses significant safety concerns. In a recent report, Di Roberto et al. from ETH Zurich devised a screening method for CAR T-cell cancer immunotherapy based on modifying antigen-binding of the CAR scFv domain and downstream signaling to discriminate between healthy and tumor cells.

The group first created a reporter line where they inserted a GFP transgene into the endogenous IL-2 gene of B3Z T cells, which displayed dose-dependent activation in response to a T-cell activation cocktail. Next, they targeted the TCR variable β chain complementarity determining region (CDRβ3) within this reporter line for targeted insertion of a fluorescent reporter as well as scFv genes against model antigens, including HER2 breast cancer antigen. They confirmed that these cells expressed the integrated constructs sufficiently on the surface and were responsive to their respective antigen. Through co-culture experiments with high, medium and low HER2-expressing cells, the group demonstrated that the B3Z T cells expressing a HER2-specific CAR were still significantly activated in the presence of modest expression of antigen mirroring healthy cells. The group then used a diverse library of scFv variants to examine antigen-binding affinity and downstream signaling, and how discrimination between tumor cells and healthy cells could be achieved. In one approach, they screened based on binding affinity to a soluble antigen to find strong and weak binding CARs. In their second, functional approach, they screened their library on the basis of IL-2 response to co-cultures with a HER2-expressing tumor cell line. Through iterative rounds of screening, they identified variants from the functional screen capable of distinguishing between tumor and normal cell lines, with no differences in activation in the presence of the tumor cell line. Furthermore, they did not find a correlation between antigen binding affinity and activation, demonstrating that functional-based screening was a superior strategy for screening CAR T variants.

In contrast to other strategies that employ combinatorial antigen recognition or administration of soluble targeting molecules, which can be tricky to generate and administer in a clinical setting, the authors show that modification of a single genomic target site can overcome significant therapeutic barriers. This work serves as an example of ways that screening strategies can be simplified and eventually aid in the search for more effective and safe cell-based therapeutics.

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Society News


New Patient Education Site Includes More Resources

ASGCT is proud to announce the launch of a brand new Patient Education site, which now hosts all of the program's existing resources as well as new resources on vectors, disease treatments, clinical trials, and more. We're excited that this site allows the educational content to be more user friendly, dynamic, and appealing.

This is the third group of resources from ASGCT's Patient Education Program. This week, we highlighted the four types of viral vectors on the Vectors 101 page. During this round, we'll also release new pages, videos, and infographics on:

Let us know what you think of the new site and collection of resources by sending feedback to ASGCT Patient Outreach Manager Ali Kujawski.

Don't Miss Dr. Anthony Fauci at Next Week's COVID-19 Symposium

There's still time to register if you'd like to attend our complimentary COVID-19 Symposium. During the virtual event, our invited speakers will highlight the advances in understanding SARS-CoV-2 and treating COVID-19. Additionally, those who submitted abstracts will discuss their brand new research. We're excited to welcome Anthony Fauci, M.D., Director of the National Institute of Allergy and Infectious Diseases, who will kick off the evenet with a keynote address on the research response to COVID-19. Check out the agenda and register now!

Associate Members: Attend the 2020 Policy Summit for $25

For the first time, ASGCT is offering an Associate Member registration fee of just $25 for the 2020 Policy Summit! Rates to attend the full 2.5 days of the Summit are $150 for Members, and $250 for non members. Join us for an exciting program featuring discussions on key policy challenges and opportunities in the development of, access to, and responsible use of gene and cell therapies. Register now!

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Career Center


Are you looking for a job in the field of gene and cell therapy? Check out the new ASGCT Career Center for great opportunities with industry, government, and academic organizations. Sign up to receive alerts for open jobs in your area.

If you're from a recruiting institution, advertise in the Featured Jobs section to target the 4,000+ audience of The Vector.

Featured Jobs

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Public Policy


Recent Policy Developments Align With ASGCT Positions on Patient Access

Over the past month, two developments line up with positions for which ASGCT has advocated, marking successes in addressing patient access issues for gene and cell therapies:

  • On August 11, the Oklahoma Health Care Authority officially withdrew its application for the Healthy Adult Opportunity (HAO) program, which allows states to create Medicaid demonstration projects with provisions such as a change from per-patient reimbursement to a predefined capped budget approach. ASGCT had submitted a letter to the Centers for Medicare & Medicaid Services (CMS) earlier this summer expressing concerns that this program could restrict access to gene and cell therapies.
  • In the fiscal year 2021 Inpatient Prospective Payment System (IPPS) final rule issued last week, CMS created a new Medicare Severity-Diagnosis Related Group (MS-DRG) for CAR T-cell therapy. When calculating the average cost of the therapy, CMS used an atypical methodology that excluded clinical trial claims, which ASGCT supported since it more adequately reimburses providers for FDA-approved CAR T-cell therapies than the typical rate-setting methodology would have. In preparation for the robust pipeline of gene and cell therapies to be approved, ASGCT will continue to work toward additional policies to promote access for Medicare beneficiaries.

ASGCT Makes Recommendations to FDA on PDUFA Reauthorization

Last month, ASGCT submitted comments to the FDA on the reauthorization of the Prescription Drug User Fee Act (PDUFA) Public Meeting held in July. The act, reauthorized every five years, authorizes FDA to collect user fees from companies that produce certain human drug and biological products. The reauthorization process includes FDA engagement with stakeholders to develop FDA performance goals for the five-year period.

ASGCT recommendations to FDA included to:

  • Allocate additional user fees to CBER, since current PDUFA funding growth has not kept pace with current and expected workload increases at CBER.
  • Utilize additional user fee dollars for increasing CBER review staff and improving FDA’s recruitment, training, and retention strategies.
  • Improve engagement of FDA with sponsors to enhance regulatory predictability by developing optional CBER-sponsor communication plans early in the development of RMAT- or breakthrough-designated products.
  • Provide guidance documents on the requirements for clinical immunogenicity testing for AAV gene therapies and CMC requirements for clinical-stage manufacturing changes for gene and cell therapy products.

International Efforts Progress on Heritable Germline Gene Editing

On August 19, ASGCT submitted comments to a public consultation period on the World Health Organization’s (WHO) Draft Governance Framework for Human Genome Editing. In these comments ASGCT reiterated its position that the clinical use of germline gene editing should not currently be allowed and encouraged the WHO to continue to emphasize its interim recommendation that “it would be irresponsible at this time for anyone to proceed with clinical applications of human germline genome editing.” The Society also restated its position that somatic cell gene editing should not be subjected to an undue burden of scrutiny that is not applied to other innovative therapies, and that it generally opposes additional accreditation, registration, or licensing requirements for somatic cell editing that exceed those applied to other therapeutic products in countries with frameworks in place for regulating gene therapy, including gene editing. The WHO will release at least one more draft for comment before finalization.

In addition, the International Commission on the Clinical Use of Human Germline Genome Editing released its final consensus study report on September 3—Heritable Human Genome Editing. One conclusion of the report, published by the National Academy of Medicine, the National Academy of Sciences, and the Royal Society, is that significant knowledge gaps remain concerning how to control and characterize genome editing in human zygotes, thereby making heritable uses unacceptable at this time. This conclusion is congruent with ASGCT’s position statement on the issue. While the report’s broad conclusion is that heritable clinical uses should not be allowed at this time, the Commission finds the issue is too complex and significant to fail to plan for a time when those safety and efficacy problems may be overcome, so it provides criteria for consideration for the future. Other highlights include a recommendation to establish an international scientific advisory panel to provide independent review of scientific evidence. Additionally, the report recommends establishing an accessible and anonymous international whistleblower mechanism, which ASGCT has supported.

Industry News


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2020

ASGCT Policy Summit

September 23-25, 2020