Friday, 5 June 2015



The race to cure cancer using our own immune system

Chemotherapy is a barbaric therapy - its like killing a wasp biting a human with a machine gun. To kill the 3% of rogue cells kill everything in sight. The biggest irony: the very immune system that provides some chance of survival is destroyed by the poisonous 'therapy'. Using the brilliant engineering of an existing immune system to identify and kill cancer cells heralds the dawn of a new age in cancer therapeutics and will finally bury the horrific body poisonings. These therapies come under the umbrella of Adoptive T Cell Therapy and are called Chimeric Antigen Receptor CAR T cell, T Cell Receptor TCR and Tumor Infiltrating Lymphocyte TIL therapies.
Illus 2
From the website of Adaptimmune - the strategy of CAR and TCR to target cancer cells using engineered T-cells
One of the most successful in these new therapies is CAR T cells therapy which stands for chimeric antigen receptors. There is a race to launch cures for multiple types of blood cancer using this therapy. It has not yet shown similar responses in solid cancers and does trigger a cytokine storm (a side effect) that can be fatal if not managed adequately. All the trials where this therapy has been used have been nothing short of miraculous with some success rates achieving remission in 90% of the cases. A brief description of CAR Ts therapy as provided in an article in The Scientist: The premise is simple: extract a patient’s T cells (our immune system's killer cells) from blood and train them to recognize and kill cancer by modifying them with a viral vector to express an artificial, or chimeric, receptor specific for a particular cancer-associated antigen—for example CD19, an antigen expressed in B-cell–related blood cancers—then reinfuse the cells back into the patient. The virus DNA is modified to remove any functions that harm us. A virus naturally fuses with a T-Cell injecting certain gene code into the T cells which then express on its surface receptors which have specific affinity towards surface proteins expressed on a particular cancer cell. The engineered cells recognize, bind and kill cancerous cells, while reactivating other immune players that have been dampened by cancer’s inhibitory signals. “CAR therapy is at the same time cell therapy, gene therapy, and immunotherapy,” says Michel Sadelain, a founding director of Memorial Sloan Kettering’s Center for Cell Engineering and a cofounder of Juno. “It represents a radical departure from all forms of medicine in existence until now.”

A case study of Emily Whitehead as reported by Michael Herper in Forbes brings the potential of this therapy to the fore:

Emily Whitehead was diagnosed at 5 with acute lymphoblastic leukemia. She suffered an infection from her first round of chemotherapy and nearly lost her legs. Then the cancer came back; she was put into remission once more and scheduled for a bone marrow transplant. As she waited, the cancer returned yet again. There was nothing else to try.

Nothing except a crazy experimental treatment never before given to a child: Blood was taken out of 6-year-old Emily’s body, passed through a machine to remove her white cells and put back in. Then scientists at the University of Pennsylvania used a modified HIV virus to genetically reprogram those white cells so that they would attack her cancer, and reinjected them. Emily suffered from the side effect a immune response storm which made her severely feverish and on the verge of death but a rheumatoid arthritis drug stopped the side effect without protecting the cancer. The therapy performed a miracle - on her 7th birthday Emily was pronounced cancer free! She still is, two years later–taking piano lessons, wrestling with her dog and loving school, which she couldn’t attend while sick. “I’ve been an oncologist for 20 years,” says Stephan Grupp her doctor, “and I have never, ever seen anything like this.”

Some of the key Players in Adoptive Cell Therapy in no particular order:
Kite Pharma
Lion Biotech
SQZ Biotech
immatics Biotech
Go Therapeutics
Peregrine Pharma
Tilt Biotherapeutics
BioNTech - Cell & Gene Therapies (subsidiary)
Eureka Therapeutics
Unum Therapeutics
Stage Cell Therapeutics (acquired by Juno)
FF CanVac
Cell Medica
Sangamo Biosciences

Most of them are spin outs from Universities and have a deal with major Pharma companies which are also mentioned below.

Some of the clinical trial successes that spurred the frenzy of research and deals with big Pharma in this field:

2011: In 2011, the Penn group described the results of an early trial of its CTL019 CAR T-cell treatment in three advanced chronic lymphocytic leukemia (CLL) patients (Sci Transl Med, 3:95ra73, 2011). The findings—including two patients who have now remained in remission 4.5 years after their treatment—served as an early demonstration that CAR T cells can successfully treat patients with late-stage disease. The team has now tested CAR T-cell therapies in about 125 people, with six different trials underway for pediatric and adult ALL, CLL, multiple myeloma, and non-Hodgkin’s lymphoma. Other CAR T-cell therapies are in trials for solid tumors, including ovarian, breast, and pancreatic cancers, and mesothelioma and glioblastoma.

2014: In a recent Penn study of 30 children and adults with relapsed or refractory ALL who received CTL019, 90 percent achieved total remission, and 78 percent were still living at the end of the study two years later (NEJM, 371:1507-17, 2014)

2014: At ASH (American Society of Haemotology), Dr. Grupp discussed a follow-up study, including 39 pediatric patients, which showed a 92 percent complete remission rate following CTL019 treatment. Of those, 76 percent remain in complete remission after six months (ASH 2014, Abstract 380, 2014)

2014: A team at the National Cancer Institute, including Dr. Rosenberg, has also reported successes with CAR T cell therapy, focusing on patients with refractory diffuse large B-cell lymphoma, an aggressive disease for which survival without treatment is measured in months. Following treatment with CD19-targeting T cells, 22 of 27 patients had either complete or partial remissions; 10 have remained cancer free for up to 37 months (ASH 2014, Abstract 550, 2014)

2014: in preliminary results from a 10-patient study on synovial sarcoma, Adaptimmune's treatment among the 5 patients who have reached the 60-day assessment period, 80% charted a response to the treatment, with one patient's cancer completely gone at 9 months. All of the infusions have been well-tolerated.

December 2014: in an ongoing Phase 1 trial, its chimeric antigen receptor (CAR) T-cell therapy, JCAR015, put 24 of 27 adults with refractive acute lymphoblastic leukemia (ALL) into remission, with six patients remaining disease free for more than a year - done by Juno

Now let us look at some of these brilliant warriors battling against the dreaded disease:

1. UPENN: Foremost name that should be mentioned is Dr. Carl June rated as one of the most influential people in biopharma today and is the Director of translational research, University of Pennsylvania. He first introduced to the world results of 3 patients treated with CAR T cell therapy in 2011. Since then he and his team have conducted successful trials of different types of blood cancers.
NOVARTIS paid US$ 20 million as part of its much larger licensing and research deal with University of Pennsylvania with regards to CAR T cell therapy and then bought Dendrion's closed facility to manufacture the therapy. They are jointly building a 30,000 sq ft Center for Advanced Cellular Therapies focused on research in developing CAR T cell therapies and going after more diseases. What is exciting for Novartis is that UPenn team used the same technology against HIV virus and Phase I trial proved that the therapy is safe and does resist HIV virus proliferation without needing ADT. To augment the development of lentiviral vectors for the CART 19 therapy Novartis also signed a US$ 350 million deal with Oxford Biomedica.
Penn and Novartis were facing lawsuits filed by St. Judes Childrens Hospital and Juno on its intellectual property rights. This was settled out of court this April 2015 whereby Novartis agreed to pay upfront US$ 12.5 mil plus royalties on global sales of these products.

2. JUNO THERAPEUTICS: From June to Juno. Six founding scientists each having brilliant track record leading to expertise in CAR T cell therapies and TCR therapies joined hands to form Juno. They are in the process of developing second generation CAR T cell therapy called Armored CARTs. These would help dynamically control the side effects of the therapy and also be useful in the environment of solid tumors. They are in Phase I/II of many CD19 and WT-1 targets. It is in preclinical for various other targets. Juno's fund raising trajectory has also been as exciting as its therapeutics one: launched with US$ 120 million led by Arch Venture Partners followed by another round of US$ 145 including Venrock and Jeff Bezos (Amazon) in Jan 2014 which later expanded to US$ 176 million as Series A in April 2014. Within 4 months it raised another US$ 134 million round B from a clutch of institutional investors. By December 2014 it had completed an IPO to raise US$ 305 million. At recent price its market capitalization doubled to US$ 4.7 billion - all in a year!

3. KITE PHARMA: The first CAR T cell therapy was developed in Weizmann Institute of Science in Israel in 1980s by Zelig Eshhar. He later joined hands in this research with Steven Rosenberg. Both these are now playing advisory roles to Kite Pharma. Kite has CAR, TCR and therapeutic vaccine therapies. It has reached Phase II trials for CAR CD19 and NY-ESO-i TCR and in Phase I and preclinical for 3 CAR and 5 TCR targets. Along with Amgen it is increasing its targets to multiple other cancers including solid tumors. Kite started with US$ 15 million from investors like David Bonderman (TPG) and Michael Milken. It did  series A in May 2013 for a total of US$ 35 million (fresh as well as converted capital). In April 2014 it raised US$ 50 million as pre-IPO mezz finance and in mid 2014 it raised US$ 146 million from listing on NASDAQ. It did a follow on offering at $54 per share (much above IPO price of $17/share) to raise additional US$ 216 million. Its current market capitalization is US$ 2.37 billion
AMGEN: in Jan 2015 Kite and Amgen signed a collaboration agreement which paid Kite upfront US$ 60 million plus royalty and milestone payments of US$ 525 million accruing to both.

4. CELECTIS: The brain behind Celectis is a pioneer in the analysis and use of meganucleases to edit genes. This is a key enabling technology for adoptive cell therapy. It has one product in clinical trial and three in preclinicals. It raised 20.5 million Euros in early 2014 from a few funds and investors. In November it raised another 13 million Euros. Celectis licensed Ohio State University's CS1 related CAR technology in Jan 2015. The company listed its shares as ADS on NASDAQ  and raised US$ 228 million in March 2015. Its market capitalization is US$ 1.4 billion.
PFIZER: In June 2014 Celectis entered into a collaboration and licensing agreement with Pfizer wherein it received an upfront payment of US$ 80 million plus research costs for 12 targets selected by Pfizer plus US$ 185 million milestone based payments per product commercialized by Pfizer along with royalties from its sales. Pfizer also bought a 10% stake in Celectis.

5. BELLICUM: Was founded by Dr. Kevin Slavin and Dr. David Spencer. Bellicum uses its proprietary CID technology which allows it to modulate the activation or deactivation of CAR, TCR and Dendritic therapies. This becomes 2nd Gen as it allows these therapies to be administered in a controlled manner. It has two candidates in Phase II and III and three in preclinical stages. Its funding journey began with a grant in 2011 of US$ 6.1 million followed by series B of US$ 20 million in 2 phases in 2012. It raised an additional US$ 14.7 million in Jan 2014. In August 2014 it raised US$ 55 million series C round. In a December 2014 IPO it raised US$ 160 million. Its current market cap is US$ 650 million.

6. IMMUNOCORE: Oxford University scientist Dr. Bent Jacobsen can also be counted as one of the pioneers of today's hottest cancer therapies - he has been researching immune receptors since 1993. His research and technology enhancing the affinity of CAR and TCR therapies has led to the formation of 2 highly successful biotechnology companies Adaptimmune and Immunocore. Immunocore has the exclusive rights to apply this technology for TCR therapies. According to them CAR targets (surface proteins) comprise of only 10% of cancer cells whereas Immunocore's TCR targets (HLA Peptide Complex) comprise of 90% of cancer cell's expressed targets and can also be intracellular. So their therapy called ImmTACs is claimed to have 9 times more chances of binding T cells to cancer cells and destroying them. They also multiply the affinity manifold towards targets to further improve the efficacy. It has one target in Phase II and one target in Phase I clinical trials.
GENETECH + ROCHE: Immunocore signed a licensing and drug development deal in mid 2013 wherein it will receive upfront payments of US$ 10 -20 million per target therapy plus milestone related payments amounting to US$ 300 million plus multi-tiered royalties on sales.
GSK: After one month of the Genetech agreement Immunocore signed a deal with GSK for multiple novel targets not addressable using antibody based therapies. It will receive 142 million GBP as preclinical payments and 200 million GBP in milestone related payments plus double digit royalties on sales. Within 4 months of signing Immunocore reached its first milestone.
ELI LILLY: in mid 2014 Immunocore signed a co-discovery and co-development deal with Eli Lilly whereby it will receive upfront payments of US$ 15 million per program for the discovery and  If Lilly accepts a preclinical candidate package to develop and potentially commercialize, Immunocore will receive an opt-in fee of $10 million and will have an option to continue co-development with Lilly on a cost-sharing and profitsharing basis. If Immunocore does not exercise its option, it will be entitled to potential future significant milestone and royalty payments.
MEDIMMUNE + ASTRAZENECA: Deal involves upfront payment to Immunocore of US$ 20 million per programme plus milestone related payments of US$ 300 million plus significant royalties on sales.

7. ADAPTIMMUNE: Sister company to Immunocore with James Noble choosing to head this solely rather than have an oversight on both. Adaptimmune's TCR technology can target both intracellular and extracellular target cancer proteins which according to them increases the number of targets multi-fold vis-a-vis to CAR therapy. TCR engineering is the core strength of the company. Their lead TCR candidate NY-ESO-1 is in Phase I and II trials for 5 cancer targets including solid tumors.Besides these 5 it has 2 more in preclinical stage. In their recent clinical trial results declared on NY-ESO-1 with regards to multiple myeloma and synovial sarcoma they have observed 60% response amongst patients in the trial. From only  1 million GBP in June 2014 it raised US$ 104 million Series A led by New Enterprise Associates and including many other investors including existing investor University of Oxford. In May 2015 it raised US$ 220 million with an IPO. Its current market cap is US$ 1 billion.
GSK: In a deal closed in June 2014 GSK agreed to pay Adaptimmune US$ 350 million in 7 years based on reaching development milestones along with additional payments in subsequent years plus royalties in single and double digit on tiered basis.