The Vector

Volume 9, Issue 4: April 2020


Editorial Team

Melvin Rincon, M.D., Ph.D. – Editor, The Vector
Edith Pfister, Ph.D. – Associate Editor, The Vector
Karen Bulaklak, Ph.D. – Junior Editor, The Vector

Inside This Issue

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

Leadership Message

ASGCT Will Hold First-Ever Virtual Annual Meeting 

I hope that you and your loved ones are staying safe while we work together, separately, to help others stay healthy. I think we can all agree that the last few weeks have been challenging as all of us around the world continue to navigate new circumstances. Though a lot of unknowns remain, we’re excited to have officially moved the ASGCT Annual Meeting to a virtual event and to ensure ASGCT is able to share a full year’s worth of important scientific advancement. With that in mind, we are looking forward to hosting ASGCT’s first-ever virtual meeting, as scheduled, on May 12-15, 2020.

We realize that this is not the meeting that any of us expected. However, ASGCT’s 23rd Annual Meeting remains on-pace to host the largest collection of abstracts in Society history by a staggering 50 percent. We can provide additional scheduling details as they’re finalized, but the Annual Meeting will include a combination of live-streamed events (including the pre-meeting workshops and plenary sessions), pre-recorded talks with live Q&A, a virtual career fair, and a virtual exhibit hall. 

I know that you still might have questions about this new meeting format, and I promise that we are working to address them. The information we have about this change is available here, and we’ll continue to provide updates in the days ahead. I’d like to thank all of you for being patient while we work to bring you the best possible meeting experience that we can.

Meanwhile, if you haven’t already voted in the 2020 Board of Directors election, the polls close tomorrow, April 10! If you’re a full or transitional member, please visit this section of the ASGCT website to learn more about the candidates and cast your vote. The future of the Society depends on you!

Thank you for continuing to support ASGCT. I appreciate the work you all do.

 

Sincerely,

Guangping Gao, Ph.D.
ASGCT President

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Breaking Through

Oncolytic Adenovirus Armed with BiTE, Cytokine, and Checkpoint Inhibitor Enables CAR T Cells to Control the Growth of Heterogeneous Tumors

Porter CE, Rosewell Shaw A, Jung Y, Yip T, Castro PD, Sandulache VC, Sikora A, Gottschalk S, Ittman MM, Brenner MK, Suzuki M

DOI: https://doi.org/10.1016/j.ymthe.2020.02.016

Summary by Karen Bulaklak, Ph.D.​

CAR-T therapies have shown great success, particularly for hematological malignancies, with two FDA-approved therapies currently on the market. Still, targeting of solid tumors remains a challenge due to factors such as target antigen heterogeneity, an immunosuppressive tumor microenvironment, and poor infiltration of tumor-infiltrating lymphocytes into the stroma. To overcome such issues, Porter and colleagues from Baylor College of Medicine and St. Jude Children’s Research Hospital generated a multimodal system to target solid tumors and engage native and CAR-T cells to elicit anti-tumor activity. Their multifaceted therapy is composed of a helper-dependent adenovirus (HDAd) encoding a bispecific T-cell engager (BiTE), a PD-L1 blocking antibody, and IL-12p70 proinflammatory cytokine, which they termed “HDAdTrio.” Each of these components serves to engage T cells and target cells via linkage of the T-cell CD3 receptor with a tumor-expressed molecule, block self-antigens expressed on the surface of tumor cells, and increase T-cell infiltration into the tumor site, respectively. To confirm BiTE specificity, the researchers first showed that treatment with a HDAdBiTE (BiTE alone) targeted at the CD44v6 molecule led to destruction of CD44v6+ HNSCC tumor cells when co-cultured with non-transduced T cells, suggesting that T cell-mediated recognition and killing had occurred. On the other hand, the fully loaded HDAdTrio significantly increased anti-tumor activity compared to HDAdBiTE and HDAdDuo (PD-L1 blocking/IL-12p70 alone) and determined that both CD4 and CD8 T cells were involved in creating a cytotoxic effect. Further transcriptional profiling of these T cells revealed that both subsets expressed activation markers LAG3, TIM3, and CTLA-4, as well as T helper (Th)1-related genes, which are associated with T cell exhaustion.

The researchers next explored the possibility of dual antigen targeting using HDAdTrio and T cells expressing a transgenic CAR against the HER2 receptor (HER2.CARTs). Co-culture of HDAdTrio-infected CD44v6+/HER2+ tumor cells and HER2.CARTs reduced tumor cell viability compared to infection with HDAdBiTE or HDAdDuo. Additionally, they saw a reduction in cytotoxicity in CD44v6+/HER2- tumor cells with the treatment, which was similar to results from HDAdTrio-infected tumor cells co-cultured with non-transduced T cells. To test this system in vivo, HDAdTrio or HDAdDuo and an oncolytic adenovirus (CAdTrio or CAdDuo, respectively) were used to pre-treat HER2+ tumor cells, which were injected into NSG mice. After administration of antigen-specific CARTs, tumor growth slowed with both CAdTrio and CAdDuo, with no obvious differences between the two constructs. When tested in an orthotopic model that presents both primary and metastatic HER2+ tumors, CAdTrio with HER2.CART administration resulted in a noticeable reduction in tumor volume and improved survival. Finally, HER2- cells were transplanted into the orthotopic model to determine if the therapy was still efficacious at eliminating tumor cells that did not possess the CAR T antigen. Interestingly, CAdTrio/HER2.CART treatment reduced tumor volume and extended median survival compared to CAdDuo/HER2.CART and any single treatment modality alone. However, while a reduction in primary tumor volume was observed, residual metastatic growths were apparent over time. The researchers point to the NSG model used, which does not create a normal anti-tumor host response like immunocompetent mice. While work is underway to address such limitations, the authors describe a novel, multifunctional treatment to kill tumor cells directly, modulate the local tumor microenvironment and engage circulating T cells and CAR T cells. While it is still too early to tell, such an approach has the potential to overcome many challenges in treating solid tumors and brings us a step closer to finding a cure.

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Society News


Tomorrow is the Last Day to Vote in the ASGCT Election

If you're a full or transitional member, use your voice to direct ASGCT's path forward! Cast your ballot by Friday, April 10, for the candidates looking to fill five open positions on the Board of Directors. You can learn more about the candidates and vote here.

Catch Up on ASGCT March News 

Last month was Endometriosis Awareness Month as well as Women's History Month. To explore these important issues, two members of the ASGCT Communications Committee contributed pieces to our blog. Read about the potential impact gene and cell therapy could have on endometriosis treatment, and why we need more women in leadership roles at each level of the gene therapy pipeline.

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Career Center


Are you looking for a job in the field of gene and cell therapy? Check out the ASGCT Job Bank and 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 3,000+ audience of The Vector.

Featured Jobs

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Public Policy


Effects of COVID-19 on the Field: Guidance and Resources Are Available

The FDA and NIH have issued a number of guidance documents that relate to how the COVID-19 pandemic is affecting our members, including how researchers and developers should proceed with clinical trials and research funding requirements. FDA documents include guidance on reporting requirements for contingency measures and the use of non-invasive patient monitoring technology. You can also find NIH guidance, as well as clinician and patient resources, here.

ASGCT Emphasizes Gene Therapy Needs in Regulation and Research Funding

ASGCT submitted comments last month to the FDA on a draft guidance, Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products. Highlights include ASGCT's recommendation that FDA indicate validated biomarkers, i.e., those listed in the Table of Surrogate Endpoints, are acceptable endpoints for traditional approval of gene therapies. The Society also encouraged the FDA to indicate that for rare disease, historical controls or retrospective natural history data may be appropriate to demonstrate effectiveness. In addition, ASGCT suggested that FDA include as an example of strong mechanistic support (requiring one adequate and well-controlled clinical investigation) not only enzyme replacement therapy, but also gene therapy for enzyme deficiencies.

In line with the Society’s strategic priorities, ASGCT is increasing its engagement with the NIH. In response to a request for information from the National Institute for Deafness and Communication Disorders (NIDCD) on its next strategic plan, ASGCT submitted comments last month. Comments indicated that gene therapy was among the greatest scientific discoveries over the last five years in the treatment of hearing and balance disorders and is key among the unmet research needs in the field. Areas of particular need for further research funding include vector refinement and development, in-depth natural history studies of sensorineural disorders, and development of improved preclinical cell and animal models.

Newborn Screening Advocacy is Successful

On March 20, the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) was re-established as a discretionary advisory committee. The ACHDNC is a critical component of the federal process to recommend diseases for state screening programs, but its authority to meet had lapsed late last year. ASGCT signed on to a letter to HHS Secretary Alexander Azar in December, led by the March of Dimes, to encourage this resumption of committee activities.

The Society also signed on last month to a letter supporting HB 1054 in the Georgia legislature, led by the EveryLife Foundation for Rare Diseases. The bill would expedite newborn screening in Georgia by ensuring that all federal Recommended Uniform Screening Panel (RUSP) conditions are added to the state’s screening panel in a reasonable amount of time with the appropriate funding. The measure passed the House, and the COVID-19 pandemic has delayed its consideration in the Senate.

Industry News


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2022

ASGCT 25th Annual Meeting

May 16-19, 2022

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