First Author Conversations

In this episode, Dr. Geoffrey Lynn talks about the development of a polymer-based antigen delivery technology- SNAP, or self-assembling nanoparticles, displaying a patient’s own neoantigens to induce a CD8 T-cell response and tumor regression in animal models. The work was published on Nature Biotechnology on Jan. 13th 2020, “Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens”.

Geoff first introduced personalized cancer vaccines. He then explained how one class of therapies- checkpoint inhibitors unleashes the immune system to attack cancer.

“Now the reason why precision medicine or personalized therapy is important is because… each cancer is going to have a unique set of mutations…, if we want to leverage the immune system, we may have to target a unique set of cancer antigens or these mutations which are often referred to as neoantigens”.

By sequencing DNA and RNAs from a tumor, as well as using bioinformatics methods, one can identify predicted peptide neoantigens, and create a patient specific vaccine.

We discussed the different delivery vehicles for personalized cancer vaccines. “When you have a peptide antigen, that's exactly what you want to display to the immune system. So there's no concern that if you have a DNA, RNA expression system or virus that your antigen won't be expressed in vivo… They [peptide antigens] are a very modular platform.”

Geoff further explained how his team was able to stimulate a stronger immune response by combing peptide antigens with specific adjuvants, Toll-like receptor 7/8 agonist.

The final challenge they tackled in this work is the amino acid sequence variability and physical/chemical heterogeneity of peptide neoantigens. This is why SNAP technology is developed and where SNAP comes in handy. SNAP links neoantigens to a polymer that self-assemble into the same particle size, the same amounts of peptide antigen in each particle, and the same overall charge of the particle. Geoff specifically acknowledged GenScript’s support in building thousands of peptides for them to evaluate and develop SNAP technology, especially “peptide antigens that are very rare, are the most hydrophobic, the most charged, and the most hydrophilic”, Geoff said, “this allowed us to really prove the versatility of the technology; so that was quite critical to really convincing us as well as potential funders, that we've really addressed this issue of allowing for consistent formulations with any peptide antigen.”

Dr. Lynn is the CEO of Avidea Technologies. This publication is also highlighted in a BioWorld article, “Standardized delivery of unique neoantigens improves T-cell vaccines”.

On Oct. 7th, 2019, the Nobel Assembly announced that William G. Kaelin, Jr., Dana-Farber Cancer Institute, shares the 2019 Nobel Prize in Physiology or Medicine with Sir Peter J. Ratcliffe of Oxford University and the Francis Crick Institute, and Gregg L. Semenza of Johns Hopkins University, for their discoveries of how cells sense and adapt to oxygen availability. 

In this episode Tracy interviews Hilary Nicholson, Ph.D., a postdoc research fellow in Kaelin Lab at Dana-Farber Cancer Institute. Hilary talked about her perspectives of Dr. Kaelin receiving the Nobel Prize, how Dr. Kaelin mentors and inspires her, and how her work is built upon this textbook discovery.

Hilary is the first author of a recent publication on Science Signaling, "HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species". Kidney cancer is one of the top ten most common forms of cancer in developed countries, and the most common type of kidney cancer is clear cell renal cell carcinoma (ccRCC). The von Hippel-Lindau tumor suppressor gene (VHL) inactivation is associated with ccRCC development, and hypoxia-inducible factor 2 alpha (HIF-2 alpha) is accumulated. 

Hilary talks about synthetic lethality between CDK4/6 inhibition and VHL loss in two species and across various human ccRCC cell lines in culture and xenografts; The study also shows that HIF-2 alpha was not required for the synthetic lethality. "These findings support testing CDK4/6 inhibitors as treatment for ccRCC, alone and in combination with HIF-2 alpha inhibitors".

In addition, Hilary introduced the Science Cheer leaders, a non-profit organization comprised of 300+ current and former NFL, NBA and college cheerleaders pursuing STEM careers.

Genome editing technologies have proliferated in recent years as have different types of immunotherapies. What possibilities exist at the intersection of these advances? In this episode Tracy interviews Theo Roth, Marson Lab at UCSF.

Theo is the first author on a recent paper in Nature entitled Reprogramming Human T-Cell Function and Specificity With Non Viral Genome Targeting.

In recent episodes of this podcast we have discussed manipulating the stemness of T-cells as well as identifying populations of T-cells that are reactive to tumor neo-antigens. Here, we are talking about rapidly engineering immune cell genomes. How quickly can in be done (in terms of helping a patient) and what are the limitations on the scale of changes that could be made? Can it be done without the use of viral vectors?

Theo describes the work to "knock-in" new sequences and ensure they integrate in the correct locations, under the correct regulation.

There is already some evidence that successful immunotherapy is probably connected with reactivity against neo-antigens. But can we identify a population of T-cells whose receptors are specific to those antigens and take further advantage of those to create more effective immunotherapies for individuals?

Anna Pasetto is the first author on a recent publication in Cancer Immunology Research titled Tumor and Neo-Antigen Reactive T-cell Receptors Can be Identified Based on their Frequency in Fresh Tumor.

She and her co-authors hypothesized that the predominant clonotypes within a population of T-cells may indicate its tumor reactivity. 

Anna describes for Tracy the strategy they used to identify the candidate clonotypes using deep sequencing of TCRB, single cell PCR and statistical analysis in figuring out which alpha chain was paired with which beta chain in the predominant receptor class.

This research is promising for increasing the effectiveness of cell based immuno-therapies.

Synthetic biology shows promise in areas as diverse as food and fuels. Nathan Hillson from the U.S. Department of Energy's (DOE) Joint BioEnergy Institute and his team recently published a paper in ACS Synthetic Biology titled, Parallel Integration and Chromosomal Expansion of Metabolic Pathways.

...synthetic biology is really just kind of a cultural mindset. So, it's looking into biology more from an engineering type of a perspective…more on the use-inspired side of things. - Nathan Hillson

Using synthetic biology to produce fuels has seen a lot of improvements, but while fossil fuels remain relatively inexpensive, that may not make economic sense.

However, it may be competitive in the area of producing materials that can go into flavors and fragrances, or lubricants etc.

In this episode, Tracy talks to Nathan about the process of using synthetic biology to produce materials on a large scale from engineering pathways into bacteria or fungi and testing the optimal mix of pathway components to maximize production.

He talks about overcoming challenges such as strain stability or reduced production from chromosomally integrated pathways.

Finally, Nathan describes the role of the DOE's Agile BioFoundry in developing a common infrastructure  on which private companies can then address specific problems.

Cell-based therapies against cancer are becoming more common. Many of those rely on manipulation of T-cells. Is it possible to select a population of T-cells that are more vigorous and better at killing tumor cells?

In this episode, Tracy interviews Suman Vodnala about inducing "stemness" in T-cells to make them perform better in terms of proliferation, persistence and effectiveness. This preserves the potential of the T-cell to do its job. These findings were published in a recent issue of Science.

While this can be done pharmacologically, Suman Kumar Vodnala, Ph.D., National Cancer Institute, describes how manipulating specific ions (potassium) in the growth medium can have a similar effect.

Suman and Tracy also discuss other ways in which T-cells might be kept alive longer.

More than 40 million people are infected with HIV. While the rate of new infections has decreased, and effective antiretroviral drug therapy is available, resource-poor settings in regions of the developing may limit the access to lifesaving drugs. Hence, in the absence of drug therapy, HIV-infected individuals may die in a matter of 10 years or less.

Despite tremendous efforts to develop a truly effective HIV vaccine and curative therapy, alternative approaches are being investigated.

In this episode, we talk to Dr. Sebastian P. Fuchs and Dr. Jose M. Martinez-Navio from University of Miami who recently published a paper in the journal Immunity reporting a functional cure of a SHIV-infected monkey. Their approach involved adeno-associated virus (AAV)-mediated delivery of broadly neutralizing antibodies against HIV. A one-time injection that leads to the production of antibodies is an alternative immunization approach where the anti-HIV immune response is "transported" to the individual.

The authors also discuss challenges of the approach (a host immune response against the encoded antibodies) and what problems remain to be solved before a clinical trial is realistic.