Gene therapy, by definition, is the replacement of a malfunctioning or missing gene to correct a genetic disease. While several gene therapies have been approved for monogenic diseases, therapies targeting more complex polygenic diseases pose challenges. For example, if the expression of a specific ligand is downregulated in the disease state, simply increasing ligand expression via a gene vector may not be sufficient to ameliorate the disease if receptor expression is also downregulated due to low intrinsic ligand expression. In other words, correcting a single gene deficiency is likely not sufficient to reverse or improve the disease state if multiple genes are involved. Recently, groups from Cambridge University and University of Melbourne published a proof-of-concept paper1 where they successfully demonstrated gene expression of 2 genes delivered using a single adeno-associated virus (AAV).
While a combination gene therapy approach has been published before2, it has utilized individual vectors to deliver each gene. A study from George Church’s lab showed that a combination of 3 genes associated with increasing longevity – FGF21, αKlotho and soluble TGFβ receptor2 – had a positive impact on 4 age related diseases including obesity, type 2 diabetes, heart failure and renal failure. Systemic delivery of AAVs singly or in various combinations showed a positive effect on all 4 disease models. The combination of TGFβ receptor2 and FGF21 expression showed synergistic improvement of therapeutic efficacy in all 4 diseases, but the combination of FGF21 and αKlotho had a negative effect on the renal and heart failure disease models. This interesting finding suggests that designing gene combinations should be done carefully and validated in preclinical models for synergy. Nevertheless, the study by Davidsohn et al. highlight a new approach to gene therapy for polygenic diseases but this approach has some limitation including differences in expression level of the individual genes that are under the control of different promoters and concerns with viral burden.
The recent work from Khatib et al. has advanced combination gene therapy by combining expression of 2 genes in a single viral vector under the control of one promoter – BDNF or brain derived neurotrophic factor and its receptor TrkB. The two open reading frames are separated by a viral 2A peptide that is cleaved by the host cell machinery resulting in the expression of both genes in the same cell and at similar expression levels. This novel viral vector was tested in 2 animal models of disease – experimental glaucoma and tauopathy. Glaucoma is an optic neuropathy that causes optic nerve damage so the glaucoma phenotype was induced via injury to the optic nerve. The increased expression of both BDNF and TrkB was shown to improve axonal transport along the optic nerve compared to single expression of each gene and there was improved vision suggesting that this combination gene therapy could potentially restore vision loss due to glaucoma.
There have been reports that showed correlation in amyloid-related pathology in the eye and brain so the effect of improved axonal transport along the optic nerve was tested in the P301S mouse model of tauopathy measured by measurement of improvement of short-term and long-term memory. The study showed moderate increase in short-term memory after AAV administration but no significant change in long-term memory.
It is clear that combination gene therapies have the potential to improve gene therapy and there are signs of pharma interest in this area. The group from Cambridge University spun out a company called Quethera that is focused on the next generation of combination gene therapies. Astellas recently acquired Quethera in a deal valued at up to $109M34suggesting that combination gene therapies for polygenic diseases is the next frontier of gene therapy development.
References:
1Khatib et al. Receptor-ligand supplementation via a self-cleaving 2A peptide–based gene therapy promotes CNS axonal transport with functional recovery Science Advances 31 Mar 2021: Vol. 7, no. 14, eabd2590.
2Davidsohn et al. A single combination gene therapy treats multiple age-related diseases. Proceedings of the National Academy of Sciences Nov 2019, 116 (47) 23505-23511.
The SARS-CoV2 virus has been the major focus of scientific research as well as the predominant news story since early 2020. One of the biggest concerns with the SARS-CoV2 virus is the emergence of new and more potent variant strains due to mutations in the viral genome. When the virus infects and replicates in host cells, new mutations appear in the genome. Most of the mutations do not have functional consequences such as increased infectivity or immune evasion. However, there are some mutations that improve viral infectivity or disease spread resulting in the development of new variant strains. The SARS-CoV2 genome is a single strand of positive sense RNA that encodes genes required to build new viral particles. The primary proteins of interest encoded by the viral genome are the spike, envelope and membrane proteins as well as 2 replicase polyproteins1. Mutations in the spike protein are of high interest as the spike protein binds to the host ACE2 protein (angiotensin converting enzyme 2) prior to entering the cell. Once the virus is in the host cell, it hijacks the translational machinery to replicate and then new viral particles are released to repeat the infection-replication-release cycle.
Currently, there are 4 strains that are considered “variants of concern” in the US2– the alpha, beta, gamma and delta variants. The delta variant is currently the most common variant in the US and is of significant concern as it is highly contagious and can be spread by vaccinated individuals. Additionally, the available vaccines may not be sufficiently efficacious against the delta variant3. The amino acid changes in each variant have been identified and published4 and interestingly several changes are convergent where the same change arises independently in multiple variant lineages. One example is the N501Y mutation that has been identified in the alpha, beta and gamma variants. Conversely, variant specific mutations that have functional consequences have been identified – a couple of examples are the L452R and E484Q mutations in the delta variant that have been show to affect recognition by antibodies4.
The scientific community is currently focused on characterizing emerging variants especially the strains that are more contagious or cause more severe disease. Some of the new variants of interest that have been identified in the past few months include the eta, iota, kappa and lambda strains. The lambda strain has been of particular interest due to 2 amino acid changes (T76I and L452Q) that increase infectivity and a unique 7 amino acid deleted in the N-terminal of the spike protein that helps evade neutralizing antibodies5. Along with the characterization of emerging variants, there is a great deal of interest in developing reliable methods to predict future variants. One approach is to analyze genomic surveillance datasets where the viral genome sequences are compared over time to identify changes and high frequency mutations across multiple regions and multiple countries, based on a recent report6. This study used a complex combination of biological and epidemiological parameters to build a forecasting model to predict mutations in the SARS-CoV2 spike protein6. The most forecasted mutations have shown increase in frequency globally and this data is useful for ongoing analysis of whether the available vaccines can trigger the formation of neutralizing antibodies against the new variants. One school of thought is that the new variants will be derived from the contagious delta variant, which has been able to evade the immune system but this hypothesis will need to be validated in more detail using forecasting models and epidemiological data.
Given the rapid rate of mutation of the SARS-CoV2 virus and emergence of new strains, it is clear that the scientific community has to continue to refine forecasting models based on real-world data, and work collaboratively to stay ahead of the ever-changing SARS-CoV2 virus and manage the global pandemic.
Finding new therapies for neurological diseases has always posed challenges, and while there has been some drug success stories, neurological diseases no longer attract much pharma or venture capital investment1. There is no doubt that a neurodegenerative disease like Alzheimer’s disease (AD) has enormous unmet clinical needs but repeated clinical trial failures have reduced pharma interest in developing disease-modifying therapies2. Additionally, the pathophysiology of diseases like AD are very complicated since symptoms like memory loss, cognitive dysfunction etc. manifest in later stages. Because the early stages of the disease are asymptomatic, it is almost impossible to identify patients with very early-stage disease who can be enrolled in clinical trials for disease-modifying therapies. Due to the complexity and high failure rate in the clinic, many pharma companies like Pfizer, Amgen and Astra Zeneca backed away from neuroscience drug development1, likely due to the fact that there were no short-term gains to be had. Biogen, however, went against the trend and continued working on a drug called aducanumab that targeted b-amyloid plaques that are a hallmark of AD. Aducanumab is a monoclonal antibody that enters the brain at low concentrations where it binds to the b-amyloid plaques and triggers immune-mediated clearance of the plaques. The hypothesis is that if the plaques reduce, cognitive decline will also slow down and may even reach a plateau.
The initial phase I and II clinical trial data on aducanumab looked promising but an interim analysis of a phase III trial in early-stage AD patient with mild symptoms, predicted that the drug would not meet the primary endpoints3. Aducanumab seemed to be destined to join the scrap heap of failed AD drugs, but in an surprising reversal, Biogen announced that after analyzing a larger data set, the drug did reduce clinical decline in AD patients when given at high doses4. Expectedly, this volte face triggered a great deal of discussion as to how the larger data set showed a completely different outcome compared to the interim readouts. Nevertheless, in June 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease5 and the drug is now available under the brand name Aduhelm. The approval is conditional in that ongoing post-approval studies are ongoing and need to demonstrate clinical benefits. If these shows do not show definitive clinical benefit, the FDA may revoke approval. Understandably, the approval is quite controversial and many clinicians are not ready to prescribe the drug and payors like Medicare are not willing to pay the steep price6.
While Aduhelm is receiving both positive and negative attention, the approval decision has triggered renewed interest in Alzheimer’s disease drug programs. For example, Eli Lilly is filing for approval of their AD drug candidate, donanemab and companies like Bristol Myers Squibb (BMS) and GlaxoSmithKline (GSK) are signing deals to bring new AD drug candidates7. BMS is working on licensing in a new anti-tau therapy from Prothena and GSK signed a deal with Alector Pharmaceuticals to develop drug candidates for Alzheimer’s disease and Parkinson’s disease8. Aduhelm’s accelerated approval could pave the way to overcoming other challenges as well. The regulatory approval path that Biogen took could potentially serve as a blueprint for the next-generation of AD therapies. If payors are willing to accept the high price point of Aduhelm (estimated at $56,000 a year), it will likely set a precedent for other AD therapies. Additionally, if the post-approval studies show that plaque clearance does improve cognition and has clinical benefits, this will open the doors for innovative new drugs that can clear plaques efficiently in early- and even mid-stage AD patients. If Aduhelm and the next-generation of AD drugs are shown to work, the benefits to millions of AD patients and their families will be incalculable.
One of the biggest challenges in developing antiviral therapies or vaccines is the propensity of viruses to mutate. In many cases, the nucleic acid or protein target in the virus changes significantly so the vaccine or therapy is no longer effective. This viral escape effect requires a constant cycle of vaccine development and therapies which have a high impact on cost, timeline and clinical needs. A high throughput model to predict the mutation patterns in viruses has not been developed using conventional experimental methods. These techniques are time consuming where single virus strains are profiled and it is not possible to analyze the effect of multiple mutations on a virus. However, there has been a recent breakthrough by a group at MIT that used Natural Language Processing (NLP) to develop models to identify mutations in viruses and just as important, identify areas that are less likely to mutate1.
Natural language processing (NLP) includes machine learning algorithms that were originally developed to understand human languages. Simply put, NLP is the ability of a computer to analyze and manipulate human languages. Human languages follow set grammar rules so the underlying hypothesis of the work done at MIT is that the same principles used in a language model can be used to analyze viral proteins. Some of the key hypotheses that were used in the study included a) semantics changes in the language model corresponded to antigenic changes; b) the grammaticality (or conformity to set grammar rules) of the language model translates to viral fitness and c) both these elements together help predict viral escape. The complex model was used to search for mutations in three well known viral proteins – influenza A hemagglutinin (HA) protein, the HIV-1 envelope protein and the SARS-CoV-2 spike protein. These proteins are responsible for binding to target cells and are widely studied drug targets. Therefore, it is important to understand the viral escape associated with these proteins in order to better design antiviral therapies.
The model showed striking results in all 3 proteins. The HA protein consists of a globular head and stalk domain and it has been experimentally shown that the head protein is more like to mutate compared to the stalk. The NLP model confirmed this finding and also supports the development of neutralizing antibodies that target the protein stalk. Similarly, the V1/V2 regions of the HIV-1 envelope protein were also confirmed by the model to be susceptible to mutations and consequently viral escape potential. One point to note is that the model in its current form detects genetic mutations leading to amino acid changes and does not account for post translational modifications like glycosylation or phosphorylation. The SARS-CoV-2 spike protein was predicted to have the highest mutation rates and escape potential in the N-terminal and receptor binding (S1) domains while the S2 subunit was predicted to be more stable and less likely to mutate. However, one question that remains unanswered the rate at which the SARS-CoV-2 virus mutates but given the reports on newly identified mutations, the findings from this model could be further refined to predict the best antigen targets for long lasting vaccine development.
The model relies on the fact that the evolution of viruses is based on maintaining viral fitness to continue the replication and infection cycle while escaping detection by the host’s immune system – a viral Darwin’s theory of the survival of the fittest. The NLP model has several advantages in that only genetic sequence information is required instead of complex tertiary protein structures and the amount of input data is modest. For this proof-of-concept study, 60,000 HIV sequences, 45,000 influenza A sequences and 4,000 SARS-CoV-2 sequences were used2. The potential for using this model is enormous as genetic sequence data is fast and relatively inexpensive to generate compared to complex protein analysis. The MIT group’s is currently working on identifying targets for tumor vaccines2 but as this model improves it can be used for AI based drug design of novel therapies to overcome drug resistance.
References:
1Hie et al. Learning the language of viral evolution and escape. Science (2021); 371:6526, 284-288.
The development of vaccines and therapeutics against the novel SARS-CoV2 virus have dominated global news and drug development efforts since the novel coronavirus has changed the lifestyle of almost every person on the planet. The current standard of care for patients infected with SARS-CoV2 includes oxygen therapy and ventilation to assist in respiration along with dexamethasone (a steroid) and remdesivir, an antiviral therapy that has so far shown limited efficacy. Given the high incidence rate and hospitalization rate, there is a strong momentum to repurpose existing antiviral therapies that have known safety profiles to treat COVID-19.
Typical antiviral drugs target viral proteins, so the long-term efficacy of these drugs can reduce if the targeted viral proteins mutate such that they are no longer inhibited by the antiviral therapy. A new approach to developing therapies against SARS-CoV2 is to target host cell machinery. Coronaviruses like SARS-CoV2 are large RNA viruses so once they infect the cell via attachment of the spike protein to cell surface receptors, the first step is for the genomic RNA to be uncoated from the viral capsid and translated to functional proteins. Some of the proteins form the viral replication transcription complex, while others are involved in mRNA translational control and proteolytic cleavage. Essentially, the virus hijacks the host cell translational machinery to start its replication cycle.
A recent report from Kris White and colleagues at the Icahn School of Medicine at Mount Sinai showcases an example of repurposing an oncology therapeutic, plitidepsin (Aplidin®), for COVID-191. Plitidepsin inhibits eEF1A or eukaryotic Elongation Factor 1A that is a critical component of the translation machinery. Plitidepsin is a member of the didemnins class of compounds and is a cyclic depsipeptide (which is a peptide that forms a cyclic structure via an ester bond). It was originally extracted from Aplidium albicans, a rare sea squirt found in the shallow waters off the coast of Ibiza, Spain and is being clinically tested to treat multiple myeloma patients in conjunction with dexamethasone. In a phase III trial, patients treated with plitidepsin and dexamethasone had a 35% reduction in disease progression compared to dexamethasone alone2. Additionally, plitidepsin was found to have a good safety profile with the most common side effects being fatigue, muscle pain and nausea3.
Plitidepsin was tested in in vitro and in vivo models of SARS-CoV2 and was found to be over 25-fold more potent than remdesivir that has received emergency use authorization to treat patients with COVID-19. Through the use of drug resistant mutant eEF1A, the researchers identified that the effect on SARS-CoV2 was due to the inhibition of eEF1A function in the translational machinery. Plitidepsin was also found to reduce viral protein expression in infected cell lines. Following the cell line data, the researchers tested the effects of plitidepsin in 2 mouse models of SARS-CoV2 and showed reductions in viral load and lung inflammation in plitidepsin treated mice1. PharmaMar, the company that developed plitidepsin for cancer indications has recently completed a clinical trial where the efficacy of plitidepsin on COVID-19 was evaluated on 46 COVID-19 patients who had required hospitalization. The study results were dramatic and showed an average 70% reduction in viral load 15 days post treatment along with reduction in inflammation and clinical improvement.
Based on these reports that demonstrate efficacy, plitidepsin appears to be a viable therapeutic for COVID-19 with a good safety profile. This is another example of a therapy identified in a marine animal that can be a game changer in the fight against disease.
Progeria or Hutchinson-Gilford syndrome is a rare disease characterized by accelerated dramatic aging. It is estimated that one in 4 million live births have progeria, and currently about 400 children have been diagnosed with the disease. Progeria does not develop at birth and symptoms appear about a year after birth, and the average lifespan of progeria patients is 14 years. Along with characteristic physical features such as a large head, small facial features and baldness, children with progeria suffer from joint issues and heart diseases that can lead to fatal heart attacks or stroke. In 2003, scientists discovered that a single point mutation (GGC > GGT) in the Lamin A gene was the genetic disease driver of progeria1. The point mutation resulted in the truncation of the Lamin A protein causing destabilization of the nuclear membranes in cells. The truncated Lamin A protein is also called progerin. The impact of nuclear membrane destabilization results in dysregulated transcription, mitochondrial dysfunction and accelerated cell death and senescence. The effects are prominently seen in tissues subject to external forces such as cardiovascular and musculoskeletal tissues.
There is a genomic test to identify the presence of point mutations in the Lamin A gene (LMNA) clinically, and this facilitates early diagnosis and treatment. In November 2020, the first therapy for progeria was approved by the FDA2 – lonafarnib (Zokinvy) was developed by Eiger BioPharmaceuticals and is a farnesyltransferase inhibitor. Lonafarnib acts by inhibiting the farnesylation of the progerin protein (truncated Lamin A) so that it does not bind to the nuclear membrane and this helps reduce the destabilization of the nuclear membrane3. Lonafarnib was found to increase the lifespan of progeria patients by 2.5 years in the 11 year follow up time frame of the trial cohort compared to natural history controls. Due to its inhibitory effect on truncated Lamin A protein, lonfarnib is also being investigated as a potential therapy for other rare laminopathies.
Recently, researchers at Harvard University and the Broad Institute published a ground-breaking new study using CRISPR based DNA editing technology to correct the point mutation in Lamin A4. Conventional CRISPR Cas9 system nicks both strands of DNA at specific locations allowing the insertion or deletion of a DNA sequence but it does not correct point mutations. David Liu’s lab at the Broad Institute has advanced CRISPR technology to develop single strand base editing capabilities, which were successfully shown to correct the point mutation in Lamin A. Base editing technology uses engineered bacterial deaminase enzymes that convert an adenine (A) base to cytosine (C) and a guanine (G) to thymidine (T). The deaminase enzymes are targeted to the DNA sequence that requires editing by the Cas9 enzyme that performs the same function in conventional CRISPR technology.
The researchers delivered the base editing system via adeno-associated viruses (AAV) to correct the error in the Lamin A gene in mouse models of progeria, resulting in an increase in the amount of normal Lamin A protein in the heart and muscles. This correction resulted in doubling of the lifespan of treated mice compared to control despite the efficiency of base correction being in the 20-60% range5. The study demonstrated a critical point that 100% efficiency of correction is not required to see improvement in the disease phenotype. While minimal off target effects were detected in this study, safety issues must be thoroughly investigated before using base editing in human patients.
Nevertheless, this study demonstrates that pinpoint accuracy of DNA sequence correction can be a ground breaking approach to fix disease causing point mutations and improve patient quality of life and increase life span6.
Idiopathic pulmonary fibrosis (IPF) is a rare but serious lung disease with an estimated 5,000 new cases each year and over 100,000 patients in the US1. IPF is characterized by the development of thick scar tissues in the interstitial spaces in the lungs that results in reduced gas exchange over time. Over time, the air sacs or alveoli in the lungs are replaced with stiff scar tissue. Essentially, IPF is the result of a disbalance between epithelial cells and fibroblasts resulting in increased fibrosis in lung tissues. It has been suggested that IPF develops due to repeated injury by unknown factors to the lung epithelial cells resulting in wound formation. As the name suggest, a definitive disease driver has not been identified for IPF but risk factors have been identified including a family history of interstitial lung disease, smoking, gastroesophageal reflux disease (GERD), age (older than 50 years) and gender (75% of IPF patients are male).
Oxygen therapy and lifestyle management help delay disease progression but if IPF progresses to a severe stage, a lung transplant may be the only available option but there are some pharmaceutical options. Currently, there are 2 drugs on the market for IPF – nintedanib (Ofev®) from Boehringer Ingelheim and pirfenidone (Esbriet®) from Roche. Nintedanib is a broad tyrosine kinase inhibitor that binds to and inhibits activation of tyrosine kinase receptors like FGFR (fibroblast growth factor receptor), VEGFR (vascular endothelial growth factor receptor) and PDGFR (platelet derived growth factor receptor), that are important for fibroblast proliferation and migration as well as the development of the extracellular matrix (ECM)2. Pirfenidone is an anti-inflammatory agent that also reduces fibroblast proliferation and inhibits the production of specific collagen forms. While pirfenidone have been shown to extend life span by 2.5 years3, and nintedanib and pirfenidone have been shown to slow the decline in lung function.
In the past couple of years, promising new therapies for IPF have been moving into the clinic. PRM-151 is currently in phase III clinical trials. This therapy was originally developed by Promedior, which was acquired by Roche in 20194. PRM-151 was shown to delay and reverse pulmonary fibrosis in phase II trials suggesting that this therapy may have disease modifying potential. PRM-151 is a recombinant protein called pentraxin-2 that is associated with normal wound repair that would minimize fibrosis and scar tissue formation. Another new therapy from Galapagos NV is being tested in a proof-of-concept Phase II trial in 68 IPF patients5. The novel therapy is GLPG1205 that is an antagonist of a G-protein coupled receptor called GPR84 that has been implicated in chronic inflammatory diseases.
Additionally, there is a new therapy that is going into the clinic – Endeavor Medicines recently raised $62 million series A funding to evaluate taladegib, a small molecule inhibitor of the Hedgehog pathway in IPF patients in phase II trials6. The company plans to first evaluate the efficacy and safety of taladegib as a monotherapy and then test in combination with currently available therapies such as nintedanib or pirfenidone. Hedgehog signaling is a well-studied signaling pathways involved in development and the Sonic Hedgehog (SHH) pathway is involved in lung development including lung branching and the survival of the mesenchyme cells. A 2012 study confirmed that the Hedgehog pathway is reactivated in IPF and the downstream transcription factors GLI1 and GLI2 were accumulated in the nuclei of fibrotic cells7. Furthermore, when fibroblasts derived from IPF patients were cultured in vitro and treated with recombinant SHH, they showed a remarkable resistance to apoptosis, which may play a role in increasing lung fibrosis.
These new therapies that have disease-modifying potential could be the much-needed breakthrough that IPF patients have been waiting for.
7 Bolaños AL, Milla CM, Lira JC, Ramirez R, Checa M, Barrera L, García-Alvarez J, Carbajal V, Becerril C, Gaxiola M, Pardo A, Selman M. Role of Sonic Hedgehog in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 303: L978 –L990, 2012.
20 | Apr | 2021
The question often asked of business leaders is “what keeps you up at night?” One of the answers to that question was made obvious last year and continues to be on the list. COVID. Through management oversight, diligence, and some luck, we’ve been able to weather the pandemic storm, so far. As Dr. Fauci is fond of reminding us “don’t spike the ball on the 5 yard line”. With the focus now on moving forward with the broader availability of vaccines, the question now is whether we should consider mandating vaccines.
Many schools and universities have already made the decision to require vaccination. I wouldn’t suggest that we set company policy by what comes out of the Vatican, but the Pope was recently quoted as saying it was our moral obligation to be vaccinated. While the average age of an employee at Biomere falls within the range of what the CDC might consider to be at lower risk of becoming seriously ill, we recently have taken the step to incentivize all employees to get their shots by offering a $50 gift card to everyone receiving their first dose by July 4th (some symbolism in the date). We will cross the bridge over mandating the vaccine once we gather further research and deliberate with some outside consultation on what is in the best interests of our employees, their families, our clients, animals, and the business. Just one more thing to consider when going through the list of items in the middle of the night.
01 | Apr | 2021
CAR-T or chimeric antigen therapy T-cells are a major breakthrough in personalized cancer therapies. The premise of CAR-T is that a patient’s T-cells are isolated, genetically engineered to express a receptor that binds to tumor cells and reintroduced into the circulation to specifically attack and kill tumor cells. This approach has been successful and currently 2 CAR-T therapies are commercially available for hematological cancers. The first therapy, Kymriah® (tisagenlecleucel) was approved in 2018 for certain pediatric and young adult patients with refractory or relapsed acute lymphoblastic leukemia (ALL)1. Yescarta® (axicabtagene ciloleucel) was the second CAR-T therapy approved for certain diffuse large B-cell lymphomas (DLBCL), a specific type of non-Hodgkin’s lymphoma2. While CAR-T therapies have been successful in hematological cancers, the treatment of solid tumors has been more challenging and several novel approaches are being used to develop next-generation CAR-T therapies for solid and hematological cancers. One such approach is the use of gamma delta T cells as the source for genetically engineered CAR-T cells.
Gamma delta T-cells are a rare population (1-5%) of T-cells in the peripheral blood. These cells express T-cell receptors that are composed of gamma and delta chains in contrast to the more abundant T-cells that express T-cell receptors composed of alpha and beta chains. Gamma delta T-cells are a part of the innate immune system and have the unusual and important characteristic of being activated in an MHC-independent manner. Conventional T-cells require a foreign antigen to be presented by the MHC (major histocompatibility complex) to activate a response restricting the response. Gamma delta T-cells have also been reported to have T-cell receptor independent activation in response to phosphorylated metabolites that are produced in tumor cells due to dysregulated metabolism. Another attractive characteristic of gamma delta T-cells is the preference to attack tumor cells compared to normal tissues. Gamma delta T-cells express NK (natural killer) cell receptors such as NKp44 and NKp30 that bind to ligands overexpressed on the cell surface of many tumor cells but have low expression on normal cells. Additionally, the gamma delta T-cells secrete high levels of cytokines and chemokines to induce an inflammatory response and activate other immune cells.
One of the important endpoints in immunotherapy trials is the presence of tumor infiltrating lymphocytes (TILs). Several studies have been published to identify gamma delta T-cells infiltrated in tumors. The most commonly used methods for this analysis are transcriptomic analysis of bulk tumors, immunohistochemistry analysis using an antibody against a pan-gamma delta T-cell marker and phenotypic studies. The presence and percentage of gamma delta T-cells varies between tumor types with one study reporting up to 20% of TILs being identified as gamma delta T-cells. Some studies have shown that gamma delta T-cells tend to localize around the tumor periphery suggesting that activating tumor infiltration will drive T-cell mediated tumor killing. More studies across various tumor indications will drive understanding of the presence of gamma delta T-cells in and around tumors.
The MHC independence is a major reason why gamma delta T-cells are being evaluated for T-cell based immunotherapies in an allogeneic setting. Currently, CAR-T cells are being used in an autologous setting where the patient is the T-cell donor, limiting scale up and increasing cost. In contrast, allogeneic CAR-T therapies will help increase scale of use and manage costs but the challenge is the develop of graft vs host disease in patients treated with CAR-T cells derived from other donors. Gamma delta T-cells have the potential to support allogeneic T-cell therapies and avoid graft vs host disease. It is evident that there is continued clinical interest in using gamma delta T-cell therapies to treat various tumor indications. In the past couple of years, a few Phase I clinical trials have been initiated and one of the interesting trials that is in progress is sponsored by Incysus Therapeutics where gamma delta T-cells plus standard of care chemotherapy are being tested in glioblastoma multiforme3. Given the success of Kymriah and Yescarta in hematological cancers, there are likely to be more clinical trials using engineered gamma delta T-cells for various tumor indications in the future.
Golf is often used as a metaphor for life. How a person plays the game provides insight into how they handle challenges in their personal and professional lives. There was even a book written on that exact topic about former President Trump. I happen to come across an interesting tidbit about an old golfer that you’ll recognize if you’re a fan, Chi Chi Rodriguez, who was competing in the US Open, played that year at Hazeltine Country Club outside Minneapolis. Tied for second place after the opening round, Rodriguez eventually finished 27th, a few strokes ahead of Jack Nicklaus, Arnold Palmer, and Gary Player. His caddy for the tournament was a 17-year-old local named Tommy Friedman. That’s right, the same Thomas Friedman, famed author of the book The World Is Flat.
Everyone likes to talk about globalization and the harmonization of processes when bringing new products to different markets across the globe. Regardless of the industry, it is essential that companies be integrated, and people be experienced in navigating local and international regulations. It is essential that we be able to communicate and work across cultural differences. Obvious stuff, one would think but hasn’t always been the case when companies look to expand their global footprint. Over the last few years, JOINN has performed over 60 IND enabling programs that were registered with the USFDA supporting submissions for a total of 27 Chinese pharmaceutical companies. This represents close to 50% of comparable projects that have been conducted by all Chinese CROs combined over the same period of time.
Flattening the world through effective integration is important if we are to provide our clients with an option for better and more efficient drug development. This is a centerpiece to JOINN and Biomere’s global strategy.
