The CAR-T innovators (Part 4A)
ALLO, CLLS, CYAD
Dear Readers,
This is the final (multipart) article of CAR-T series, here we will take a deeper look into the companies which are taking big leaps in innovation with CAR-T design, efficacy, manufacturing or minimising off-target effects and resistance to therapy. This final series will uncover innovator companies.
If you want to succeed you should strike out on new paths rather than travel the worn paths of accepted success-John D. Rockefeller.
Let’s understand in brief the development cycle of CAR-T, from ‘bench to bedside’:
CAR-T cells belong to the regulatory group of advanced therapy medicinal products (ATMPs). Due to the cell-/gene-based complex nature, ATMPs are far more challenging to develop than other, more defined, medicinal products. The design of CAR-Ts has evolved substantially over the years. This field is booming with significant investments. The ability to reprogram our own immune system to fight cancer has certainly created huge expectations.
Now, let’s have a look at this table detailing the clinical Trial Success Rate by clinical trial phase and therapeutic Area
It is clear that as compared to other therapeutic areas, oncology drugs face a tighter bottleneck at phase 3 results, the success rate further reduces for orphan oncology drugs (1.9%). But this graph is not indicative of CAR-T trials success rate.
Cell and tissue-engineered products are frequently associated with challenges due to their complex and unique nature. However, Novartis and Gilead made use of a number of regulatory tools (like, orphan designation, rare disease and rare pediatric disease designation, breakthrough designation, and RMAT designation in the US; orphan designation, PRIME designation, Committee for Medicinal Products for Human Use and Parallel Consultation with Regulators and Health Technology Assessment Bodies in the EU) in order to reach the market as quickly as possible.
Innovators (Part 4A)
1. Allogene Therapeutics (Nasdaq: ALLO, M.Cap US$3.5b)
Allogene Therapeutics is pioneering the development of allogeneic CAR-T therapies and believes it can revolutionise cancer treatment by making AlloCAR T™ therapy a reality for patients.
It is a clinical stage biotechnology company, launched in April 2018 by two former Kite Pharma executives. Allogene, was formed with Series A financing of $300 million from an investment consortium that includes Two River, TPG, Vida Ventures, Bellco Capital, the University of California Office of the Chief Investment Officer of the Regents, Gilead, and Pfizer.
Advancements
Therapy availability time: Their first ALPHA trial with ALLO-501 clearly showed the benefit of off-the-shelf CAR-T cells: manufacturing time can be drastically reduced from 22 days to just 5 days. In the trial, 98% of patients received ALLO-501 with an average time from enrolment to the start of therapy of five days.
They have several refinements in the design and engineering of CAR-T cells, with the aim to reduce the GvHD risk, minimise toxicity, maximise the fitness of T cells. Lets go through these advancements and their resulting benefit and any evidence (pre-clinical or clinical) to substantiate that claim:
Knockout the α-chain of the TCR and CD52 in the CAR-T design employing transcription activator-like effector nuclease (TALEN) gene-editing technology (developed by Cellectis).
Benefit: Reduce the risk of serious graft-versus-host disease (GvHD), potential risk with off-the-shelf CAR-Ts and render the CAR T product resistant to anti-CD52 antibody treatment. It allows allogenic CAR-T to stay engrafted in host in order to achieve it’s full therapeutic impact.
Validation: ALPHA Study, open-label, Phase 1 trial (NCT03939026). In an early clinical assessment of ALLO-501 and ALLO-647 reported at ASCO (JCO), no cases of GvHD were observed, and the regimen showed signs of comparable efficacy to Kymriah and Yescarta. Clinical proof-of-concept for AlloCAR-T was observed from ALPHA Ph1 study; consolidation dosing showed early promise with 75% ORR and 63% CR among patients (n=8) treated in consolidation cohorts. Pending regulatory feedback, the Company plans to move to the Phase 2 Pivotal ALPHA2 trial at the end of 2021.
TALEN, were the first gene editing technology to be used in patients for αβTCR removal, in 2015 and 2016, it entered clinics for compassionate use of a CD19 CAR for pediatric and adult ALL. Grade 2 skin GvHD was observed in one of the two compassionate use cases, and grade 1 skin GvHD in the 2 of 21 patients in the two UCART19 clinical trials. No higher grades of GvHD were observed.
TurboCARs: a novel cytokine-stimulated CAR T cell, designed to recapitulate cytokine signaling signal selectively in CAR T.
TurboCAR T cells co-express a CAR and a Turbo domain (i.e. a homodimeric cytokine receptor chimera) that transmits CAR T cell-intrinsic cytokine signals. Source: Allogene Therapeutics Benefit: Reduces toxicity and chances of GvHD. It also improves AlloCAR T cell proliferation and overcome T cell exhaustion which helps in reduction of CAR-T cell dose requirement.
Validation: Findings of preclinical studies demonstrated that ALLO-605 (first TurboCAR targeting BCMA for relapsed or refractory multiple myeloma) showed enhanced cytokine secretion, polyfunctionality, improved serial killing activity in vitro, and enhanced eradication of tumors in animal models of myeloma. The Phase 1 dose escalation portion of the IGNITE trial evaluating ALLO-605 has begun.
Recently, Allogene also presented pre-clinical finings of PD1 TurboCAR-T cells which employs two-pronged approach aimed at inhibiting immune-suppressive PD1 signaling while simultaneously transmitting immune-potentiating cytokine signaling. This will tailor Turbo CARs for solid tumors. PD1 Turbo domains are homodimeric chimeras comprised of: (1) an ectodomain derived from the PD1 receptor, (2) transmembrane (TM) and JAK-activating domain, and (3) an intracellular signaling domain containing phosphorylable tyrosine residues derived from a cytokine receptor of interest.
FDA grants Fast Track designation for ALLO-605 (July 2021). The Phase 1 dose escalation portion of the IGNITE trial evaluating ALLO-605 was initiated in Q2 2021.
ALLO 647: Anti-CD52 additional treatment delays host T Cell Recovery and minimizes chances of GvHD.
Identification of Key Target Antigens: ALLO-316 is AlloCAR-T targeting CD70. CD70 is expressed in RCC (72-80%) and hematological cancers [AML (96%), DBCL (71%), MM (63%), CLL (50%)] with normal tissue expression limited to activated lymphocytes. Pre-clinical findings in multiple in vivo models, including a PDX model suggested that CD70 CAR T cells are efficacious
Dec 2020: FDA clears IND (Investigational New Drug ) applications for ALLO-316 in renal cell carcinoma and ALLO-715 in combination with nirogacestat for MM.
Product Pipeline
Partners
On April, 2018 they enter into asset contribution agreement for Pfizer’s (NYSE: PFE) allogeneic CAR-T immunooncology portfolio. Portfolio included 16 preclinical CAR-T assets licensed from Cellectis (NASDAQ: CLLS) and Servier and one clinical asset licensed from Servier, UCART19. UCART19 utilizes the TALEN® gene-editing technology pioneered and owned by Cellectis. As a result of the deal, Pfizer will have a 25% ownership stake in Allogene.
Other Partners
Notch Therapeutics:
Employ Notch’s Engineered Thymic Niche (ETN) platform, plan to create AlloCAR™ therapy candidates from T cells or NK (natural killer) cells
Research and develop iPSC (induced pluripotent stem cell ) AlloCAR™ therapy products
SpringWorks Therapeutics:
SpringWorks’ investigational gamma secretase inhibitor (GSI), nirogacestat will be evaluated in combination with ALLO-715, our investigational anti-B-cell maturation antigen (BCMA) AlloCAR T™ therapy in patients with relapsed or refractory multiple myeloma.
Key Management People:
Arie Belldegrun, MD: Executive Chairman and Co-Founder of Allogene. Arie founded Kite Pharma, where he served as Chairman, President and Chief Executive Officer until the acquisition of Kite by Gilead Sciences in October 2017.
David Chang, MD, PhD: an extraordinary scientist, physician and life sciences business executive with over 30 years of unprecedented experience in developing cancer treatment, including the development of Yescarta. He previously served as Executive Vice President, Research & Development, and Chief Medical Officer of Kite, a Gilead Company.
Finances
The Company had USD 913.2 million in cash, cash equivalents, and investments as of June 30, 2021. Allogene continues to expect full year GAAP Operating Expenses to be between USD 300 million and USD 330 million including estimated non-cash stock-based compensation expense of USD 80 million to USD 90 million and excluding any impact from potential new business development activities.
2. Cellectis (NASDAQ: CLLS, M.Cap: US$ 650m)
Cellectis has 21 years of expertise and knowledge in nucleases and gene editing, they use TALEN® gene editing technology for its therapeutic applications.
Advancements
Cellectis aims to deliver an off-the-shelf or Universal Chimeric Antingen Receptor T-cells (UCARTs) product. UCARTs will help overcome some of the challenges of autologous CAR-T cells, like broad availability, cost-effectiveness, novel features, compatibility and consistency. They have in-house manufacturing facility for cells at GMP Raleigh and for starting materials at GMP Paris. In coming months, Cellectis also plan to expand their internal manufacturing capabilities to strengthen their manufacturing autonomy.
Why TALEN: It is ultra-precise (genomic targeting with TALEN® can be performed within a 6 base pairs range of any chosen single nucleotide in the entire genome), specific (recognition site is of 30+ base pairs long), and efficacious (for example, TCR-α can be knocked-out with over 85% efficacy in T-cells in routine) tool of gene editing. In addition, vectorization is simple and easy.
To make its off-the-shelf UCART product candidates, Cellectis implements two separate steps of T-cell engineering.
Utilising Lentivector transduction for efficient gene transfer. Delivering genes is a key step to engineer CARs. Lentiviruses have evolved to deliver their genome efficiently to their target cells (including T-cells), and then with the help viral integrase the transferred gene is efficiently integrated into the genome.
PulseAgile Electroporation technology to introduce TALEN®-enconding messenger RNA (or mRNA). Cellectis have specialised transfection technology, PulseAgile acquired from CytoPulse Sciences Inc., a Maryland-based company in 2010. PulseAgile provides a high-quality platform for delivering nuclease-encoding mRNA into T-cells.
Product Pipeline
UCART123 (AlloCAR-T) targets CD123, an antigen expressed at the surface of leukemic cells in acute myeloid leukemia (AML).
This product went through optimization of production process and thereafter received new IND number from FDA in 2019. Clinical trial in AML initiated in 2020, AMELI-01, which is a Phase 1, dose escalation study; NCT03190278
UCART22 (AlloCAR-T) targets CD22, an antigen expressed from the pre-B-cell stage of development through mature B-cells, occurs in more than 90% of patients with B-ALL (B-cell acute lymphoblastic leukemia).
FDA approved the IND application and Phase 1 clinical trial BALLI-01, dose-escalation study initiated in 2019; (NCT04150497).
UCARTCS1 (AlloCAR-T) designed for the treatment of CS1/SLAMF7-expressing hematologic malignancies.
FDA approved the IND application in Jan, 2019 to initiate MELANI-01, a Phase 1 clinical trial for the treatment of patients with R/R multiple myeloma; NCT04142619. Early preliminary data showed the expansion and persistence of UCARTCS1 and correlated with changes in relevant serum cytokines and anti-myeloma activity (data presented in 24th annual ASGCT meeting).
UCART19, ALLO-501, ALLO-715: AlloCAR-T products in joint clinical development collaboration between Servier and Allogene, which is exclusively licensed from Cellectis.
Four new UCART preclinical programs, announced on Cellectis Innovation Days, that took place May 24-28, 2021.
UCART20x22 (first allogeneic dual CAR-T) for B-cell malignancies; Cellectis anticipates the filing for IND in 2022. This dual target CAR will help to reduce target escape potential, improve cell killing with strengthened synapses.
UCARTMESO (AlloCAR-T) for mesothelin expressing solid tumors; Cellectis anticipates the filing for IND in 2022. MESO is one of the most studied targets for solid tumor treatment and has shown promising Promising preliminary clinical results.
UCARTMUC1 (AlloCAR-T) for mucin-1 expressing epithelial cancers; Next generation product candidate with multiple edits: 3 TALEN KnockOuts and 2 Knock-In.
UCARTMUC1 product is under early stage of pre-clinical development. UCARTFAP (AlloCAR-T) targeting cancer associated fibroblasts (CAFs) in the tumor microenvironment. CAFs play a central role for T-cell exclusion and immune suppression in solid tumors.
As of Aug 2021 more than 120 patients have been treated with allogeneic CAR-T cells utilizing technology developed by Cellectis.
Partners
Allogene, Servier and recently added Sanofi
According to agreement executed in May 2021, Sanofi will supply alemtuzumab, an anti-CD52 monoclonal antibody, which will be used as part of the lymphodepleting regimen in certain Cellectis’ sponsored UCART clinical trials.
Other Partners: Iovance Biotherapeutics (agreement to use specific TALEN® technology to develop gene-edited tumor infiltrating lymphocytes) and Cytovia Therapeutics (agreement to develop TALEN® gene edited iPSC-derived NK and CAR-NK cells)
Beyond UCARTs
Cellectis has strong roots in gene editing technology, TALEN and Pulse Agile technology. Beyond UCARTs, they are now expanding the power of these precise and highly efficient technologies in hematopoietic stem cells (HSCs) for genetic diseases with huge unmet needs. They refer this novel gene therapy platform as .HEAL (Watch the video to learn more). Allogenic HSC transplant can be used as a curative treatment for number of ailments like sickle cell disease, lysosomal storage disorders and primary immunodeficiencies.
Key Management People:
André Choulika, Ph.D., is one of the founders of Cellectis and served as Chief Executive Officer since the company's inception in 1999.
David Sourdive, Ph.D., is a co-founder of Cellectis and joined the Board of Directors in 2000.
Finances
As of June 30, 2021, Cellectis, including Calyxt (Cellectis is a 64.4% stockholder), had USD 257 million in consolidated cash, cash equivalents, current financial assets and restricted cash of which USD 238 million are attributable to Cellectis on a stand-alone basis. Cash runway into 2023.
As of March 2021, Pfizer has 6.5% stake of Cellectis.
3. Celyad Oncology (Nasdaq: CYAD, M.Cap: US$ 68m)
Celyad Oncology is a clinical-stage biotechnology company, pioneering a differentiated approach to the discovery and development of both autologous and allogenic CAR-T therapy candidates. It was founded in 2004. They use human NK cell receptors which, unlike traditional CAR technologies, have the potential to target a broad range of hematological malignancies and solid tumors via a human natural receptor that targets ligands present on most tumor types (this technology was originally conducted by Dartmouth College Professor Charles Sentman).
Advancements
All-in-One Vector Approach to generate CAR-T cells.
Non-gene edited allogeneic technology platforms: T cell receptor Inhibitory Molecule (TIM) or short hairpin RNAs (shRNAs). TIM is a small peptide that interferes with the ability of the TCR to signal. These technologies help to edit TCR to avoid GvHD also offer the potential to avoid HvG, allowing the CAR T cells to persist longer in the patient offering the opportunity for improved outcomes. *Graft-versus-Host disease (GvHD): donor cells attacking the patient’s healthy tissue; Host-versus-Graft (HvG): rejection of the therapy by the patient’s immune system.
Multiplexed shRNA strategy multiplexed within micro-RNA scaffolds that enabled the co-expression of the individual shRNA with a CAR and a selectable marker all driven by the same PolII promoter within a single vector. Continued preclinical development has now demonstrated proof of principle that with multiplexed shRNA technology, concurrent knockdown of up to four genes is feasible.
Design of Celyad’s all-in-one vector This single transduction, plug and play approach to CAR-T development along with the TIM or shRNA approaches helps to enable the generation of a homogenous CAR-T cell population through a single step enrichment. It simplifies the design, streamline development and manufacturing process while broadening the potential applicability of candidates. This in turn avoids multiple genetic modifications and costs associated with additional Good Manufacturing Practice (GMP) grade vectors.
TIM-based allogeneic NKG2D CAR-T candidate CYAD-101 is currently in Phase 1 development for metastatic colorectal cancer. Preliminary results from the Phase 1 alloSHRINK trial (NCT03692429) has demonstrated proof-of-concept that the non-gene edited TIM technology has the potential to knockdown signaling of the TCR complex, with no clinical GvHD observed in the first fifteen patients.
Phase 1b trial (NCT04991948) to assess the safety and clinical activity of CYAD-101 in patients with unresectable metastatic colorectal cancer, followed by pembrolizumab treatment in collaboration with Merck has also been initiated.
shRNA-based CYAD-200 series of CAR-T candidates are currently in preclinical & early clinical development; Data from preclinical studies have shown shRNA knockdown targeting CD3ζ is as effective as gene-editing methods such as CRISPR/Cas9.
CYAD-211 (first member of CYAD-200 series), which uses a single shRNA to knockdown the CD3ζ component of the TCR complex, is currently in the Phase 1 IMMUNICY-1 trial (NCT04613557). A favorable safety profile for CYAD-211 was observed at the first two dose-levels.
On R&D Day (July 20, 2021), company introduced CYAD-203, a novel allogeneic, IL-18-armored CAR-T candidate for solid tumor now in IND-enabling studies. IL-18 is a proinflammatory cytokine that directly potentiates the anti-cancer activity of CAR T cells while also altering the balance of pro- and anti-inflammatory cells within tumor tissue.
Established expertise in Good Manufacturing Practice (GMP) grade cell therapy manufacturing, located in Mont-Saint-Guibert, Belgium.
Product Pipeline
Partners
Moffitt Cancer Center: acquisition of an exclusive license for an antibody directed to Tumor-associated glycoprotein (TAG-72), which will form the basis of a T cell engager.
MSD (tradename of Merck & Co): agreement for testing anti-PD-1 therapy, KEYTRUDA® after CYAD-101 treatment for patients with refractory metastatic colorectal cancer
Celdara Medical: acquired CAR T product candidates focused on the human Natural Killer cell receptor, NKG2D and gained rights to TIM technology.
Horizon Discovery: exclusive license agreement for the use of Horizon’s SMARTvector shRNA technology platform in 2018.
Novartis: agreement for production of allogeneic CAR T cell therapies associated with two undisclosed targets in May, 2017.
Finances
As of June 30, 2021, the Company had cash and cash equivalents of USD 14.3 million
Hey thanks for the good article.
What do you think of mustang bio ??