According to the WHO, cancer remains in 2018 the second leading cause of death in the world, accounting for an estimated 9.6 millions deaths and a global economic impact estimated in 2010 at $1.16 trillion.
Even if cancer survival rates are generally increasing in our western countries, traditional treatments (radiotherapy, chemotherapy, surgery) tend to show their limitations, leading pharmaceutical companies and investors to the sprouting field of immuno-oncology considered as a promising new approach to fight cancer.
Focusing first on immune checkpoints inhibitors (ICI), pharmaceutical giants shared the market between anti-PD1 drugs (characterized by the never-ending fight for shares between Merck’s Keytruda® and Bristol Myers-Squibb’s Opdivo®), anti-PDL1 drugs (Roche’s Tecentriq®, Merck’s Bavencio®, AstraZeneca’s Imfinzi®) and anti-CTLA4 drugs (Bristol Myers-Squibb’s Yervoy®), which all showed compelling, yet incomplete clinical responses for now.
While R&D remains strongly active in this field (search for new antibodies, combination of immune checkpoints inhibitors…), investors now seem to have turned their eyes toward new horizons : CAR (Chimeric Antigen Receptor) T-cells therapies.
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CAR-T cell technology
CARs are recombinant receptor constructs transduced ex-vivo into the genome of T-cells. They are composed of an extracellular targeting domain (scFv) that recognizes a specific tumor antigen, a transmembrane domain, and an intracellular signaling domain (CD3 zeta) associated with one or more co-stimulatory domains (CD28, ICOS, 4-1BB…) providing the second signal required for complete T-cell activation. Diverse gene-editing technologies are currently used to create CAR constructs (Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9)). Once constructs have been transduced into the T-cells, the latter are expanded and finally administered by infusion to the patient.
To date, only two CAR T-cells therapies have received FDA/EMA approvals in 2017/2018 : Novartis’s Kymriah® (tisagenlecleucel) for the treatment of Acute Lymphoblastic Leukemia (ALL) and Diffuse Large B-Cell Lymphoma (DLBCL), and Gilead/Kite’s Yescarta® (axicabtagene ciloleucel) for DLBCL, both CD19-directed therapies.
These two first-in-class treatments showed unparalleled clinical efficacy in hematologic malignancies but are also frequently accompanied with life-threatening side effects including cytokine release syndrome (characterized by high fever and low blood pressure due to the release of pro-inflammatory cytokines by the CAR T-cells), and transient neurological toxicity.
However they fail to be as effective in solid tumors. Multiple factors can explain the poor clinical response : lack of specific targetable antigene, presence of physical barriers around the tumor, inefficient T-cell trafficking, presence of an immunosuppressive environment…
Given the considerable size of the solid tumor market (hematologic malignancies only represent 1/10 of the total cancer cases), dozens of biotech companies are currently leading preclinical/clinical studies to design the next generation of CAR constructs incorporating novel mechanisms to improve the safety and anti-tumor activity in solid tumors.
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The art of sophistication
Below are presented a few examples of constructs designed to face the factors previously evoked:
Designing of inhibitory CAR constructs to regulate CAR T-cells activity in case the patient experiences serious side effects or if the T-cell encounters a specific antigen expressed only by normal tissues. For example, Houston-based Bellicum Pharmaceuticals has been developing a « safety switch » designed to lead to programmed cell death, or apoptosis after rimiducid is administered.
Since solid tumors secrete chemokines unrecognized by CAR T-cells, transgenic expression of receptors for these chemokines on CARs constructs should improve T-cells trafficking toward the tumor.
Conceiving CAR T-cells equipped with an scFv able to bind monoclonal antibodies directed against tumor antigens and therefore allowing the administration of different mAbs at different moments of the therapy and reducing the risk of adverse effects by modulating the frequency of mAbs administration.
Another way is to design a construct that requires two antigens rather than one to active the CAR-T cell. Gilead recently acquired Cell Design Labs’ SynNotchTM platform for that purpose.
Production of monoclonal antibodies directed towards immune checkpoints inhibitors in order to boost the immune response.
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Allogenic vs Autologous CAR T-cells therapies
Kymriah® and Yescarta® are both autologous CAR-T cells treatments. It means thats the patient’s own T-cells are collected and engineered before being reinfused. However the manufacturing process to create the constructs faces two main challenges : it’s both time-consuming and very expensive.
Indeed, T-cells have to be extracted from the patient’s blood, shipped to cell processing plants for genetic programming, and then sent back to the treatment center for reinfusion into the patient. This delicate process takes about 2 weeks for Yescarta® et 3 weeks for Kymriah®, delay which can be critical for patients in poor condition for whom previous treatments have failed.
The manufacturing process and the small patients population also explain the expensive treatment costs. Yescarta® and Kymriah® are respectively listed at $375.000 and $475.000 per treatment, which is actually more a starting point for pricing and reimbursement negotiations with healthcare institutions than the actual price. Moreover these therapies are often associated with high ancillary costs, such as preconditioning regiments or ICU hospitalization in case of CRS which need to be taken into account.
To defuse the situation, Novartis and Gilead both announced a collaboration with U.S. Centers for Medicare and Medicaid Services to deliver an outcome-based payment model. Both companies will receive the payment only if a significant improvement has been demonstrated one month after the infusion. Nevertheless the model is still under tough negotiation on a case by case basis since the parties disagree on the delay required to observe the benefits of the treatment.
Due to the exorbitant treatment prices, Novartis and Gilead faced a setback in the UK last summer. The NICE (National Institute for Health and Care Excellence) concluded in their preliminary appraisal that Yescarta’s treatment costs were too high to be considered a cost-effective use of NHS resources (£50,000 per year of quality adjusted life (QALY) gained). A few week later, the NICE came to the same conclusion for the use of Kymriah in adults with DLBCL.
On the other side, a few companies decided to develop allogenic CAR T-cells programs, with no need for personalized manufacturing since T-cells are extracted from donors instead of the patients themselves. With this technology, they expect to produce faster and cheaper treatments for patients.
Cellectis, a french clinical-stage biotech company founded in 1999 by André Choulika decided to follow this approach. With 3 off-the-shelf/allogenic programs currently under development (UCART19, UCART 123 and UCART22), Cellectis is one of the leader in this new field. Indeed, UCART19’s phase 1 clinical trial showed an 83% complete remission rate in the population treated for ALL. However the use of allogenic T-cells raises some questions concerning their safety. In 2017, the FDA placed a clinical hold on phase 1 trials of UCART123 product candidate following the death of a patient who experienced major CRS. Another major concern with allogeneic products is graft-versus-host disease (GvHD), where the body rejects the CAR-T. Only one case of grade 1 GvHD has been reported in UCART19’s trials but it needs to be monitored carefully.
With their economical and fast manufacturing processes, pharmaceutical companies following the allogenic approach should be able to gain the biggest slice of the market. But with their strong advance, Novartis, Gilead and soon Celgene may succeed in optimizing their processes in terms of time and costs which might bring the prices of allogenic and autologous treatments close. In this case, only efficacy and safety will prevail.
However a recent move in the industry might indicate where the balance tilts. Former Kite’s executives Arie Belldegrun and David Chang founded Allogene Therapeutics last April as executive chairman and CEO respectively. Interestingly, whereas Kite first focused on autologous CAR T-cells through the development of Yescarta®, Allogene turned towards allogenic programs. The company has taken over Pfizer’s portfolio of 16 preclinical targets as well as the commercialization rights in the U.S. of UCART19, a Phase I asset co-developed by Cellectis. The company is already backed by a $300-million investment from a consortium of venture-capital and investment firms and announced in September their intent to raise $100M from U.S. IPO to pursue the development of their pipeline. Success or not, future will tell…
Guillaume Delagrée