Part 2: Global look at CAR-T trials

This post is a continuation of my initial post about clinical trial participation, where I stated:
When innovation in oncology is at an all-time high, there is now a serious short supply of clinical trial participants, particularly in cancer, leaving academic and institutional researchers, bio-tech companies and pharmaceutical companies desperate for patients to participate in their research. Approximately only 3% of adult cancer patients participate in clinical trials in the U.S.…

Taking a global macro-look, researchers and pharmaceutical companies are increasingly enrolling patients in countries outside the U.S., for example, the People’s Republic China (PRC), where significant advancements in CAR T-cell therapy are underway. Richard Brand, CFO for BeyondSpring Pharmaceuticals, believes this trend will continue going forward, especially for larger Phase 3 clinical trials. In an 11/1/2016 Life Science article, “Clinical Trials In China: A Model For Advancing Cancer Therapies,” Brand proffered:…

“Recently it has become more difficult to recruit patients for clinical trials, which is of great concern for major sponsor companies. Studies show that only 3 percent of U.S. cancer patients participate in clinical trials. As treatments have become more targeted, the desired population for clinical trials has become even more narrowly defined. Patient enrollment and retention is now a major contributing factor to the cancellation of many clinical trials. This issue presents an opportunity for companies that have a unique relationship with the China Food and Drug Administration (CFDA) and connections with hospitals in China that can generate quality data that meets U.S. Good Clinical Practice (GCP) standards. Cancer care in China continues to be highly centralized. The National Academy of Science Tumor Hospital in Beijing [aka Cancer Hospital at the Chinese Academy of Medical Sciences (CAMS), which is the first national hospital and remains the leading hospital among all cancer hospitals in China] had 800,000 patient appointments in 2015. It also treats over 2,000 new lung cancer patients each year. Unlike the U.S., where most residents have access to radiation and chemotherapy in close proximity to their homes, individuals who are diagnosed with cancer in China must travel to the advanced cancer centers that are located in Beijing, Shanghai, or Guangzhou. That limited number of advanced cancer centers often results in concentrated and rapid enrollment for clinical trial participants.”

Brand cited the following 2 examples, showing the benefits of having access to patients in China:
• In 2013, the Phase 3 global clinial trial of Boehringer Ingelheim’s lung cancer drug Giotrif (afatinib) enrolled 240 patients in China in just six months. The remaining 28 percent of the trial’s patients were recruited outside of China.
• The Phase 3 clinical trial of another drug, Icotinib (a second-/third-line non-small cell lung cancer [NSCLC] drug) enrolled 400 patients in China in just nine months.

Although the centralized care model in China can help overcome enrollment challenges in Phase 3 oncology trials, the China Food and Drug Administration (CFDA) will present challenges to the uninitiated sponsor. Established relationships with key principal investigators at the large cancer centers can greatly help a company doing business in China. In addition, qualifying a drug candidate program for Category 1 and fast-track review by the CFDA can expedite the entire process.

For those interested, the Life Science article also examines the U.S. FDA vs. CFDA regarding the matter of safety and efficacy and the China regulatory review process. The greater propensity for cancer patients in China to participate in Phase 3 clinical trials may be due in part to the CFDA’s more stringent requirements for allowing a Phase 3 trial to commence. Bender states: “China’s Phase 3 Clinical Trial Application (CTA) differs in that the CFDA requires the drug candidate to demonstrate both efficacy and safety in prior clinical trials before granting the CTA to initiate a Phase 3 trial that will enroll Chinese patients. The U.S. FDA only requires that the drug demonstrate safety in its prior trials before granting the Investigational New Drug (IND) to proceed with a Phase 3 study. In other words, China’s government further seeks to protect its people from trials with a large number of patients if a drug candidate has not demonstrated proper efficacy.”


Alexey Bersenev MD, PhD, Director of Cell Therapy Processing and Advanced Cell Therapy Laboratories at Yale-New Haven Hospital, Yale University, has done an incredible job, amassing from 10 international public databases the number of CAR T-cell therapy trials worldwide from 2004 to the end of 2016 and presented his data as follows at his website:

• A graph showing the trend in the total number of CAR cell therapy trials, listed in international databases, from 3 trials in 2007 to 116 trials in 2016.

• A bar graph showing a breakdown by Phases of CAR cell therapy trials, registered in databases, from 2007 to 2016.

The most revealing and surprising bar shows the number of CAR cell trials in the U.S. vs. China and other countries from 2009 to the end of 2016 at the following website:

• U.S. with 100% of the trials (8/8) in 2009 to 19% of trials (22/116) in 2016

• China with 0% of trials in 2009 to 72% of trials (84/116) in 2016

• Other countries with 0% in 2009 to 9% (10/116) in 2016

Dr. Bersenev also identified 38 academic institutions and hospitals as sponsors of CAR cell therapy trials in China. About half of Chinese trials, registered in 2016 were commercial (company listed as sponsor or collaborator). He provided a list of 17 identified companies.

He also mentions 6 other Chinese CAR cell therapeutic companies that were not identified in databases; three of these companies have business ties with U.S. companies, i.e.,

• 3SBio (Shenyang Sunshine Pharmaceutical Co.) CAR-T joint venture with San Diego-based Sorrento Therapeutics…

• Fosun Pharmaceutical joint venture with Kite Pharma

• JW Biotechnology (Shanghai) Co., Ltd, Juno Therapeutics’ daughter company.…

Dr. Bersenev concluded: “Overall, I’d like to conclude that China is currently dominating any other country in CAR cell therapy field in terms of total number of active trials and supporting hospitals. China also has all “latests” CAR cell technologies in trials, such as humanized scFv, 4th generation constructs, bispecific CARs, 2x CARs (CD19+CD20 or CD19+CD22 or CD19+CD30) in one treatment and so on. You can find information about many CAR cell therapy deals in China, building of manufacturing facilities and results of the trials. So, China is hot! Must follow!”


In June 2017 at the American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, where a lot of attention was expected to focus on the race between Novartis and Kite, CAR T-cell therapy demonstrated unprecedented results in several studies for myeloma patients. Although a Bluebird Bio (BLUE)/Celgene Corp. (CELG) study, testing a CAR T-cell therapy that targeted the B-cell maturation (BCMA) protein, showed an impressive overall response rate of 78% in their phase I study for relapsed/refractory myeloma patients, it was outshone by an unknown Chinese rival, Nanjing Legend Biotech, which presented the following incredible Phase I results from their ongoing Phase I clinical trial conducted at the Second Affiliated Hospital (College of Medicine) of Xi’an Jiaotong University in Xi’an, China:

• 33 out of 35 (94%) patients, whose multiple myeloma had relapsed on previous treatments, had clinical remission within two months of receiving Legend’s experimental anti-BCMA CAR-T cell product, dubbed LCAR-B38M, and the objective response rate was 100%.

• The first 35 patients enrolled in the ongoing clinical trial received three split doses (20%, 30% and 50% respectively) of cells over a week, and first signs of efficacy appeared as early as 10 days after the initial injection.

• Among the 19 patients researchers have followed for more than four months—a criterion for full efficacy assessment set by the International Myeloma Working Group—14 reached stringent complete response (sCR), meaning there’s no detectable plasma cells in the patient’s bone marrow or myeloma proteins in the serum or urine. For the other five patients, one reached partial response, and the rest four very good partial response—even though one progressed three months after extramedullary lesion disappeared. All five patients who have been followed for over a year remain in sCR status.

• In terms of safety, 85% patients experienced cytokine release syndrome (CRS), a common and potentially dangerous complication of anti-T cell injections. Researchers said the majority of those cases were mild and manageable, with only two grade 3 (severe) CRS having been observed, and the patients recovered after receiving tocilizumab. Besides, no neurologic side effects occurred so far.…

For any Bluebird Bio and Celgene investors here, the FierceBiotech article presents an informative comparison with rival Legend Biotech. Regarding the topic of my post, the article commented that perhaps because the population base in China is larger, Legend Biotech’s study has more participants so far than its rival. Fan said they plan to enroll 100 patients to this trial at four participating hospitals in China, while Bluebird’s trial plans to have half that many participants.

Now who the heck is Legend Biotech? This upstart private company was founded in 2014 by Frank Fan, who is also the chief scientific officer and claims full intellectual property rights for his company’s new therapy. For now, it is taking the autologous approach that engineers a patient’s own T-cells to target cancer cells. The largest investor in Nanjing Legend Biotech is Hong Kong-based Genscript Biotech (listed on the Hong Kong Stock Exchange), a multinational provider of contract biological research services encompassing gene synthesis and molecular biology, peptide synthesis, custom antibodies, protein expression, antibody and protein engineering, and in vitro and in vivo pharmacology. Fan related that his company plans to launch a similar clinical trial in the U.S., and they also want to explore the method in patients with newly diagnosed multiple myeloma. The company is looking for multiple financial and scientific partners to see the projects through. Fan also did not rule out the possibility of licensing out the out-of-China right to the med to another biopharma partner. A collaboration and partnership with a well-known solid U.S. firm might also allay any perception among skeptics that data from China is “unreliable” and “untrusted.” Some researchers already see Legend Biotech’s presentation and success at ASCO as a game changer for Chinese CAR-T biotech.


CAR T-cell therapy R & D is rapidly growing in number of competitors and clinical trials, primarily in China, U.S. and U.K. It’s apparent that Phase 3 in clinical trials is a critical make or break hurdle for all competitors. Picking winners now is way too premature as currently it’s still a wide open challenge, delivering viable treatments for tumor cancers to the marketplace. So far, only one CAR T-cell therapy, using the autologous approach by the University of Pennsylvania/Novartis collaboration, has received final FDA approval.



Editas (EDIT) and CRISPR (CRSP) are speculative but huge-potential startups that could use gene editing to creatively destroy the world of medicine and existing drug companies. This gene editing machine, derived from a natural defense mechanism in bateria could be a silver bullet for many diseases. Currently EDIT has a deal with Allergan (up to $1B plus royalties) for a cure for a certain blindness that is caused by extra DNA inserted in the wrong place. They will edit that out and cure the disease. Scientists have already created a mosquito that can eliminate malaria. By editing the genes, they produce a mosquito that will not support the gene in their body. What really surprised them was that the edited genes were passed on to offspring. This would allow them to overwhelm the natural mosquites (I think it was also dominant, so if they interbread, all the offspring would be malaria proof). In a short time malria and other similar disease could be eradicated. (They can also gene edit to reverse the condition and bring back the old ones if necessary). In this case, they also did an edit to make the eyes red so they could tell in the lab which were the edited mosquitos. I don’t think they released any yet.…

At special risk are gene-theray companies like Juno, Bluebird, Kite and the like. This could be a leapfrog technology like cell phones in China (imagine you are running land lines in the new China economy and all of a sudden everyone just buys a cell phone. Business time is over).

So, buy some insurance with EDIT and CRSP (not Saul stocks yet).

This is super cool and super scary stuff. It could save the human race or destroy it, like AI and Robots. Google around for it and/or check it out here TED talks are always awesome.

I learn so much cool stuff from podcasts on my bike commute to work. Highly recommend it.



Interesting research. Thank you for your update.


PuddinHead42: At special risk are gene-theray companies like Juno, Bluebird, Kite and the like.

I do not understand the above statement.

First of all, the breakthrough technology that PuddinHead42 has brought up is a genome editing technology known as CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) that allows permanent modification of genes within organisms.

Cancer research companies are using CRISPR to create chimeric antigen receptor (CAR T) and high-affinity T cell receptor (TCR) therapies to treat cancer. Back in 2015, Juno Therapeutics and Editas Medicine announced a collaboration that combined Editas’ genome editing technology and expertise and Juno’s extensive CAR T and TCR platforms.…

Also before jumping into the CAR T-cell therapy fray, Cellectis was (and still is) a gene-editing company familiar with CRISPR. When Cellectis learned about CAR T-cell therapy, they decided to separate from the pack using the autologous approach and use their gene-editing expertise to pursue their own allogeneic (universal or off-the-shelf) approach. Cellectis is currently using CRISPR/cas9 and its own TALEN, a gene editing technology, in ongoing clinical trials. Here’s a video showing how TALEN works.

On 7/24/2017, Cellectis announced the grant by the European Patent Office of patent No. EP3004337 for the invention of using RNA-guided endonucleases, such as Cas9 or Cpf1 versions of CRISPR for the genetic engineering of T-cells. The patent will be issued on August 2, 2017.…
This patent will protect the application of CRISPR gene editing to T cell research until 2034, meaning every other company doing the same will need a license from Cellectis from now on.