COVID 19: How it affects the immune system

A study published in Nature was able to shed light on the changes to the immune system in response to COVID 19 infection. Researchers in Australia were able to get serial blood samples from a patient that was hospitalized with COVID 19 and eventually recovered from the disease.

This is the first study of its kind that has looked at immune-related changes in patients with COVID 19, which provides important insights into the progression of the disease and vaccine development strategies.

The researchers analyzed a number of immune cell subsets over time: Antibody-secreting cells (ASCs), T cell subsets, Natural killer (NK) cells, and monocytes. These cells are important in mounting an anti-viral immune response, and elevated numbers of these cells are observed in patients with Ebola, SARS and H1N1 Influenza infections. Since the data was collected over multiple time-points, it provided a very comprehensive overview of how the immune system in the patient changed over time, from being symptomatic to recovery.

The researchers found that ASCs and a subset of T cells called Follicular T helper cells (TFH) cells were elevated early on in the patient’s blood, but disappeared after recovery. ASCs are key for the rapid production of antibodies following infection with the Ebola virus and vaccination against the influenza virus. and activated circulating TFH cells (cTFH cells) are concomitantly induced following vaccination against the influenza virus. Both these cell subtypes peaked in the blood 3 days before symptom resolution. Activated CD8+ T cells, increased in Ebola and influenza infections, were also increased in this case. Interestingly, there was no increase in circulating NK cells at the time-points assessed. NK cells are the first line of defense against viral infections, whose job is to activate players in the adaptive immune system (viz. CD8 T cells). It is possible that by the time this patient’s blood was evaluated, the NK cells have completed their wave. Blood draw at an earlier time-point would help clarify this point. 

What this data means: These results are important for two reasons: 1) These data provide insights on the key immune players mounting an immune response against COVID 19, which might help delineate vaccine development strategies. An ideal vaccine would mimic a natural immune response in order to clear the infection in a short period of time 2) These immune parameters could form crucial diagnostic markers for predicting response to SARS-Cov-2 infection and early identification of people who could recover from the infection. 

Immunology/ Oncology News – week of Feb 3, 2020

Kite turns out to be a concerning investment for Gilead

When Gilead acquired Kite for $12 billion (!), it was the talk of the industry for many months. It was a sign that Gilead was investing big in CAR-T cell therapy. Things have soured since, with Gilead cutting forecasts for drugs in the Kite pipeline. This was discussed in an earlier post.

This week, Gilead further cut the accounting value for research assets by $800 million, thus signaling that it is placing lower expectations on Kite’s pipeline. So far, only Yescarta from Kite has been able to generate Revenue for Gilead, but its revenues are far from making it a worthwhile investment. With the rest of the pipeline looking less promising, the Kite deal may not have been a good idea for Gilead after all.

Regeneron sets sights on coronavirus vaccine

 

In view of the World Health Organization declaring the Coronavirus outbreak a global public health emergency, more companies are entering the fray to develop a vaccine. Last week I wrote about J&J launching its vaccine development efforts. This week, Regeneron announced that it will be working in tandem with the US government to develop its own vaccines.

Regeneron definitely has a smaller global footprint than J&J w.r.t. distribution and delivery of the vaccine. However, with the US government on its side, it may very well be able to have the resources necessary to overcome that hump. At this point, it is purely a race to see who can come with a reliable vaccine in the shortest amount of time

 

Move over, CAR-T cells. CAR-NK cells next?

A small study led by MD Anderson in collaboration with Takeda has demonstrated the efficacy of CAR-NK cells in CD19+ cancers (non-Hodgkin’s lymphoma or chronic lymphocytic leukemia). The study showed similar efficacy to conventional CAR-T cell therapy that also targets CD19, but provided a way to do away with the negative effects of CAR-T cell therapy.

There are a number of advantages that CAR-NK therapy provides:

1. NK cells are the first line of defense that can later induce antigen-specific T cell responses to the tumor. Thus it leads to two waves of  ‘hits’ at the tumor, thus amplifying the overall anti-tumor immune response
2. The authors were able to use  cord blood instead of patient’s own blood. This avoids the long process of genetically modifying the patients T cells for CAR-T cell therapy, making sure patients receive treatment in a timely manner

The results from this study need to be interpreted with care, though. This was an extremely small study with only 11 patients. In addition, the patients need to be monitored for longer periods of time to look for adverse effects as well as prolonged efficacy.

Immunology/ Oncology news – Week of Jan 27 2020

Zolgensma sales grows

Novartis’ gene therapy for spinal muscular dystrophy, Zolgensma has a $2.1 Million price tag. That has not stopped it from having an impressive growth interns of revenue. With more regulatory approvals in the pipeline, this trend only appears to continue upward.

I know I only choose to write about Immunology and Oncology on this blog, but I made an exception for this bit of news because of the wider implications it has. Approval and subsequent success of one gene therapy opens the doors for the approval of several others, including CAR-T cell immunotherapy for cancers. I think we are just getting started in this space.

J&J , other pharmas launch efforts for Coronavirus vaccine

As the coronavirus spreads in China and across the globe, J&J is a leading player in trying to develop a vaccine for the virus. Of importance is the fact that if they are successful in developing a vaccine, J&J has the resources to bring production up to scale pretty quickly, making it easier to control this and any future outbreaks

 

FDA approves first drug for peanut allergy

In a landmark move, an immunotherapy for peanut allergy has been approved by the FDA. Palfozia (Aimmune Therapeutics) is an oral immunotherapy treatment that involves administering patients with increasing doses of peanut flour. Given the high risk of allergic reactions in potential patients, the first dose of Palforzia at  the very least, will need to be administered in a hospital setting under medical supervision.

The FDA approval of this drug is great news for children and teens who have accidental exposure to peanuts. However, acmes and availability of this drug does not mean that people with peanut allergies can include peanuts in their diet. People with peanut allergies still need to avoid peanuts as far as possible.

Flu vaccination to cure cancer?

Photo by CDC on Unsplash

A recent study in the journal PNAS has demonstrated that influence vaccination in cancer patients makes them more susceptible to immune checkpoint inhibitors like Keytruda. In addition, vaccination was able to change the tumor microenvironment from an immune-suppressive state to an inflammatory state.

What the authors have described here is a dual-advantage approach. While they demonstrate that influenza vaccination is able to bolster anti-tumor immunity and sensitize the cancer to immunotherapy, they also argue that vaccinating cancer patients may prevent them from future/ recurrent flu infections. This is a compelling argument since flu infections are a widespread and serious problem in cancer patients whose immune systems are weakened, making them a susceptible population.

With regards to the real-world implications of these findings, 2 things stand out :

1. The flu vaccine is already FDA-approved, thus making it easily accessible to patients for wider use
2. The authors only observed significantly effective anti-tumor immune responses when the vaccine was given intratumorally. Depending on the location of the tumor, this may not be a feasible option for all patients

AstraZeneca, Merck’s pancreatic cancer drug cleared by FDA

Pancreatic cancer is difficult to treat. While precision has helped make significant strides in improved overall survival in other cancers, pancreatic cancer has been left behind.

This week, Astra Zeneca and Merck’s Lynparza, a drug that targets the BRCA mutation, was cleared by the FDA. The BRCA mutation is found in breast and ovarian cancers. A small subset of pancreatic cancers carry this mutation too – it is this subset of patients that Lynparza will benefit from.

A study found that patients that were treated with Lynparza had almost 2-fold increase in disease-free progression compared with patients that received the placebo. However, the study only included patients that had shown previous response (i.e. no progression of the disease) after platinum-based chemotherapy. In addition, no benefit to overall survival was found in patients receiving Lynparza versus placebo.

The big picture: BRCA mutation is present in only 5-7% of patients with pancreatic cancer. Therefore, Lynparza is likely to benefit only a small subset of metastatic pancreatic cancer patients. In addition, previous studies have included only patients who have had objective response to chemotherapy, to begin with. Therefore, there is no underlying data that suggests Lynparza maybe effective in BRCA+ refractory pancreatic tumors. Regardless, the FDA clearance of Lynparza does provide relief to a specific subset of pancreatic cancer patients and provides Astra Zeneca with another revenue stream for one of its fast-growing drugs.

Low grade gliomas : Need for new therapeutic approaches

Gliomas are the most common type of brain tumors. Based on aggressiveness, they are classified as grades I- IV, with Grade IV being the most aggressive. Grade IV gliomas, also called Glioblastoma Multiforme (GBM), is one of the most aggressive cancers with a median survival of 12-16 months after surgery, chemotherapy and Radiation therapy. Understandably, GBM receives the most attention from researchers, clinicians, and advocates in terms of the development of novel therapeutic strategies.

Low-grade gliomas (LGGs, Grades I- III) differ from GBMs in their ability to lay dormant for several years before they progress to Grade IV. Because of their slow-growing nature, patients with LGGs have higher survival and better quality of life than GBM patients. A lot of times, doctors refrain from even operating on the tumor (especially if it is in a sensitive area of the brain), preferring to deal with it only when/if the tumor progresses in grade.

As a researcher in the field of brain tumor therapy development, I often get asked: “Why do you choose to focus on low-grade gliomas, when clearly the urgency is to develop new approaches for GBMs?”

Let me highlight why —

1) LGGs occur mostly in patients who are in their 20s and 30s, thus impacting them at a very young age and causing loss of productivity and pay in the prime of their life.

2) ~80% of LGGs will progress to GBM over a course of 10-15 years. Treating them at an early stage will increase the chances that they never get there.

3) The fact the LGGs can persist in our body for a prolonged period of time without detection by the immune system indicates that these tumors employ highly sophisticated mechanisms of immune suppression and immune evasion that can be exploited to develop specific therapeutic strategies.

In this age of precision medicine and immunotherapy, LGGs present a unique opportunity to explore underlying immune evasion mechanisms which can then be used to inform approaches to target them – immunotherapy or otherwise. In cancer, earlier is always better and prevention is always better than cure. LGGs provide a rare opportunity for us to treat a cancer early on – an opportunity that needs to be capitalized to its fullest.

Major events in Immunology/ Oncology – 2019

As the year winds down and the next decade is on the horizon, I thought it would be nice to take a trip down memory lane and re-visit some of the major news in the Immunology/ Oncology biotech space in 2019.

1) Celgene releases promising CAR-T data

Celgene released promising data for its CAR-T cell therapy targeting large B cell lymphoma. The therapy (liso-cel), which aims to compete with Gilead’s Yescarta and Novartis’ Kymriah, is targeted towards CD19, which is a receptor present on B cells.

The drug is expected to receive FDA approval next year.

2) Roche study boosts Merck drug’s prospects

This is a classic example of what could be achieved if pharma companies started working together. Roche, in collaboration with Paul Scherrer Institute, conducted a study to determine mechanisms of cancer metastasis. The study pointed towards CCR7, an immune cell homing marker, as a possible mechanism by which cancer cells can migrate to other niches. This led the team of scientists to believe that blocking CCR7 could be a viable approach to target cancer metastasis.

Well, Merck’s drug Navarixin, which is currently in clinical trials does just that.

It would be interesting to see what Roche and Merck do with this information in hand. The best-case scenario would be to perform collaborative studies. But most likely, Roche will try to come up with its own CCR7 blocking molecule that aims to outperform Navarixin.

3) Gilead drops anti-BCMA cell therapy

The Gilead acquisition of Kite Pharma was all over the news in 2018. This meant that Gilead was gambling hard in Kite’s CAR-T portfolio. However, things have not been rosy after the deal. With this development, Gilead has pretty much dropped the entire KITE-585 program, which was aimed to develop therapies for multiple myeloma. With the approved Yescarta sales also lagging compared to its competitors, it seems like this gamble did not pay off well for Gilead.

* Source – Fierce Biotech and Biopharma Dive

**The opinions expressed here are my humble attempts to analyze the potential implications of happenings in the biotech industry. I am in no way an industry expert, and welcome constructive criticism and counter-arguments to my opinions put forth in the article. **

Contribution of dendritic cells to the autoimmune pathology of systemic lupus erythematosus

Contribution of dendritic cells to the autoimmune pathology of systemic lupus erythematosus.

Organ transplants – to tolerate or to not tolerate?

Saints Cosmas and Damian miraculously transplant the (black) leg of a Moor onto the (white) body of Justinian. Ditzingen, 16th century
Courtesy: wikipedia.org

I just got back from a conference on regenerative medicine. The meeting featured scientists and members of the military and majority of the discussion was about the the efforts of scientists in helping wounded warriors restore their normal lives by improving organ regeneration and transplant techniques. I knew the government was invested in R&D, but this meeting made me realize how involved the military was, in researching and in funding research that would alleviate the plight of soldiers that had been wounded in action.

Limb amputations is the most common procedure performed in the battlefield and after extensive reconstructive surgery, most soldiers are looking for transplants so they can get on with their lives. Transplant rejection is a major problem plaguing organ transplants today. while advances in the field have dramatically increased the number of organs that can be transplanted and the short-term success of transplants. The long-term acceptance of grafts , however, is a different story. Not to mention the side-effects of long-term immunosuppression – infections, cancer, drug cytotoxicity – the list goes on.

However, tremendous progress is being made in the field of immunosuppression. Strategies are being developed to suppress the immune system as well as induce immune tolerance. Immune suppression commonly uses drugs to suppress the immune system as a whole, (thereby inducing aforementioned side-effects), while immune tolerance is a state where the immune system is taught to ‘tolerate’ specific antigens that might otherwise elicit a response. So what is a more desirable approach? Immune tolerance, if you ask me.

Most immune tolerance strategies rely on regulatory T cells (Tregs) or T cells that have a suppressive capacity to do their job. Tregs are extremely important for transplant survival, and the more Tregs you can get to the transplant site, the better. So most approaches (like CTLA4-Ig) that are currently in various phases of clinical trials and commercialization, involve administering antibodies that will induce Treg proliferation and migration to the graft. Another (very) important player in the immune tolerance game is dendritic cells. Dendritic cells are antigen-presenting cells. In essence, they are important in presenting antigens to T cells, and the T cells in turn react to the signals provided by the DCs. The important part is that depending on the signals the DCs give out, the T cells may either turn into reactive “cytotoxic” T cells or into suppressive Tregs. So manipulating DCs into emitting the suppressive signals has been greatly explored by research groups around the world.

What this means: Transplant research is entering an exciting era where everyday, the answers that evade long-term transplant acceptance is coming within grasp by the day. Considering how many lives can be saved and improved by organ transplants, I know that a great number of people are working really hard to get a solution. Since organ transplants play with the delicate system that our immune system is, there will likely be no quick and easy answers. We have better options for immune suppression today, than we did 20 years ago. With the tremendous amount of research being done, I can say that its only going to get better!

Donate an organ – save a life

Considering that I have been writing a research grant for the past couple weeks, its been hard for me to read about ( and even think about) anything other than organ transplants. I sincerely hope to be able to talk about the tremendous progress made in the field of organ transplants and organ regeneration. I certainly will. But today, I would like to talk about the foundation for all this research – shortage of available organs.

Every year, thousands of people die waiting for an organ that never comes. In addition, every year, thousands of people are added to the ever-growing wait-list for donor organs. Millions of dollars in funding are given out to research projects that are attempting to come up with alternative approaches to deal with organ shortage (Some of the approaches include – 3-d organ printing, cell transplant, organ regeneration and induced pluripotent stem cell (iPSc) transfer). Why? because there are not enough willing organ donors today.

Just imagine how many lives could be saved, if each one of us pledges to become an organ donor. Scientific advances have greatly increased the  number of transplantable organs. There has been tremendous progress in how long an organ can be stored in perfect condition between harvest from donor and transplant into the recipient, in order to retain maximum organ function and vitality. Most importantly, one organ donor can save as many as 8 lives. It is amazing that we have the chance to help someone live after we have died. So please, please consider becoming an organ donor.

Visit http://www.organdonor.gov/index.html for more information on how to sign up to be an organ donor.