Jumping off the CAR-Twagon: Why cell therapy may have lost a bit of its momentum

Heard of CAR-T, but wondering what happened to the space? Read on!

Source: Memorial Sloan Kettering Cancer Center

“Hope for a one-time cure”. That was the original goal with cell therapy. The space continues to hold substantial promise, and many have flocked to realize its potential: Pitchbook identifies 1000+ cell therapy companies, while 2000+ active candidates are in development. “Hope for a one-time cure” also fuels massive capital inflows, supporting a capital- and labor-intensive enterprise — by some estimates, nearly $20B in capital poured into the cell and gene therapy space in a single year.

Initially, it looked like the bet paid off. Results in hematological malignancies have been impressive: 44% OS achieved 4-years after a single infusion of Yescarta in 3L R/R large B-cell lymphoma (compared to 6.3 months mOS with standard of care), as well as 24.8 month mOS shown in multiple myeloma following Abecma treatment (vs. 9.2 months mOS ordinarily).

Yet manufacturing complexities, high costs, challenges in durability and persistence, and a difficult safety profile continue to plague this modality, limiting its widespread application. Yescarta, arguably the most established cell therapy, has delivered merely $607M in 2020 sales — a long way to go to analyst expectations of peak $1.7B by 2022.

What continues to stump researchers, investors, and entrepreneurs alike is the limited predictability of preclinical models for clinical outcomes, particularly for off-the-shelf options.

Dozens of cell-therapy upstarts have delivered impressive results in mouse models — from demonstrated engineered cell activity to target tumors, to tumor shrinkage in patient-derived xenograft mouse models — only to find limited response, dose-limiting toxicities, or longer-term relapse in clinical studies.

After taking a pulse check of the cell therapy landscape, it appears there are currently three main avenues that are being explored, and each holds its own promise and perils:

1. Autologous CAR-T: Overcoming scalability & consistency hurdles key to unlock the most efficacious (as of yet) cell therapy option

2. Allogeneic, off-the-shelf CAR-T and NK cells: Unlocking durability and persistence critical to unleashing these modalities

3. Novel cell types: Promising in theory, too early to tell in practice

Autologous CAR-T: Overcoming scalability & consistency hurdles key to unlock the most efficacious (as of yet) cell therapy option

To be fair, there have been several recent wins in ASH 2021 that cell therapy backers could point towards. Impressive event-free survival, PFS, and reduced risk of disease progression was found for both Breyanzi and Yescarta as they attempted to move into second line DLBCL, while eyebrow-raising PFS/OS findings from cilta-cel in MM suggested stiff impending competition for Abecma.

Yet the fact remains that such therapeutic upside comes with a unique set of challenges:

• Safety: Toxicity profiles of newer therapies have significantly improved — and the use of tocilizumab to manage CRS normalized — yet lethal neurotoxicity & other adverse events continue to remain a risk, as both Tmunity and Poseida have learned.
• Manufacturing capabilities and logistical complexity: Manufacturing personalized to each patient has continued to challenge the industry, creating long and inconsistent turnaround times and high COGS. Such challenges include:
  — Demand uncertainty creating capacity challenges: Insufficient manufacturing slots with a difficult-to-forecast demand necessitates early investment in capacity expansion and specialized talent recruitment
  — Limited inventory buffer: With no real inventory at the DP level, stakes are high as manufacturing must be ‘100% perfect, every time’
  — Vector sourcing for supply: For some players, vector sourcing continues to depend on external CMOs, limiting control over and speed of manufacturing
• High hospital costs: Despite the release of a new DRG, access continues to be a challenge given the high price tag of autologous therapies. Extended hospital stays induced by long, variable TATs further drive up the hospital cost burden, and in parallel limit the number of beds available for other cell therapy patients. Such cost is then compounded by the staff training needs around apheresis, lymphodepletion, and CAR-T infrastructure (cell collection, storage, handling).
• Limited efficacy in solid tumors: Despite success in improving outcomes in hematological malignances, autologous CAR-T has struggled impact solid tumors as of yet

Manufacturing capabilities remain the biggest current barrier to commercial scale

At the moment, physicians are seeking reliability in turnaround times and reproducibility in cells & doses, as delays/reschedules jeopardize an immunocompromised patient’s health. Such stipulations demand consistency and standardization in the manufacturing process, and sufficient capacity at all points. Established players have already begun re-investing in capabilities: Gilead’s Tecartus leverages a modified T-cell enrichment step vs. their Yescarta counterpart, while Novartis is developing a new “T-charge” process to reduce ex-vivo culture time and shrink TAT. In preparation for its cilta-cel launch, J&J has begun building manufacturing capabilities across China, US, and Europe, bringing lentiviral vector development in-house to reduce supply risk and conducting phased site roll-out to improve slot reliability.

Outside of autologous CAR-T, newer TCR therapies have demonstrated some promise, yet clinical results are still too early for a definitive stance. While some TCR-Ts struggle with persistence, such as Immatics’ IMA203 diminishing partial responses, others like Adaptimmune’s afami-cel and TCR2 Therapeutics’ gavo-cel have demonstrated promising initial survival and PFS data.

At the moment, it’s a race between auto CAR-T makers improving their manufacturing, and allogeneic counterparts enhancing therapeutic response rates and persistence (see below). Until off-the-shelf therapies prove enhanced efficacy/safety and educate physicians enough to switch, autologous options will remain the only viable cell therapy choice.

Allogeneic, off-the-shelf options: Unlocking durability and persistence critical to unleashing these modalities

Off-the-shelf options have long been heralded as the replacement for their complicated autologous counterparts, given the obvious benefits: reduced TAT, batch availability of starting material (i.e., an inventory buffer), potential standardization of cell source, opportunity of patient redosing, and reduced cost given simpler manufacturing/logistics to name a few. Indeed, Poseida’s switch to their P-BCMA-ALLO candidate may reflect an industry recognition that the future of cell therapy likely resides in off-the-shelf possibilities.

Yet limited persistence — often induced by T-cell exhaustion — remains the most critical hurdle

operators in this space continue to struggle inducing prolonged PFS and DOR. Alloreactivity of infused T-cells (immune rejection of grafted cells over time) has often been combatted by knock-out of MHC-1 and CD52 on allogeneic cells, yet therapeutics candidates are typically still cleared by the host NK cells by way of inhibitory KIRs.

Furthermore, off-the-shelf candidates have thus far continued to require conditioning regimens. Such myeloablative chemotherapy increases risks such as MDS, limits the potential for outpatient administration and expanded patient coverage, and steeply increase hospital costs during cell therapy administration. Such conditioning requirements have been true for both allogeneic CAR-T (to avoid GvHD) as well as NK candidates (to enhance engraftment).

Of the slate of initial clinical findings on off-the-shelf candidates, a few of the notable suspects include:

• Allogene: Initial results for ALLO-501/501A and ALLO-715 suggest potential solid duration of response for those patients who achieve CR, though longer-term durability is still to be seen
• CRISPR therapeutics: CTX110 (allo CAR-T) achieved deep responses similar to autologous CAR-T, yet durability and neurotoxicity concerns remain
• Precision biosciences: PBCAR0191 (allo CAR-T) achieved CR of 59% and ORR of 73%, yet several responders relapsed before hitting the 6 month follow-up mark.
• Fate therapeutics: Initial positive ORR of their lead candidate FT516 (CAR-NK) dropped by nearly half (70% to 45%) by the 6 month follow-up
• It should be noted that durability concerns could potentially be addressed by the NK-cells modality, but sufficient clinical outcomes have not yet been published

Encouragingly, off-the-shelf players have thus far innovated well to limit toxicity concerns of their therapeutic candidates. Safety profiles of both allogeneic CAR-Ts and particularly NK cells have been positive, in some cases eliminating CRS and neurotoxicity (as NK cells do not stimulate CRS-driving IL-6 production).

However, unless durability concerns are addressed, allogeneic therapies could be perceived as the cheaper, less complex, yet less efficacious option for patients, with the acceptance of annual (or even semi-annual) redosing — a far cry from the “one time cure” dream.

Novel cell types & approaches: Promising in theory, too early to tell in practice

Given the challenges mentioned above, new players on the block have begun exploring new cell alternatives, with great initial promise.

The first glimpse at such encouraging clinical findings reside within γδ T-cells, the cousins of the more popular αβT-cells powering traditional CAR-T. These rare cells bridge the gap between innate and adaptive immune systems, hold both regulatory and (MHC-independent) anti-tumor properties, and lack the αβTCRs that drive GvHD. Cell therapy advocates swelled at Adicet Bio’s initial Phase 1 results of their anti-CD20 AD-001 lead, which posted an impressive ORR and CR. The good news was compounded by In8bio’s 20-month remission(!) finding of its INB-100 therapeutic.

Additional alternative cell-types are also being explored:

• Boosting B-cells, our protein-production factories: These ‘protein-production factories’ offer a flexibility of roles, from functioning as antigen presenting cells to providing longevity of response. Encouragingly, this off-the-shelf option would also likely remove conditioning regimen requirements. Researchers have recently developed a method to engineer these immune cells, which was previously tricky as plasmid delivery was toxic to the cells, and to differentiate them into the right cell type (plasma B cells). Key players pioneering in this space include Be Biopharma, Walking Fish Therapeutics, and Immunosoft.
• Weaponizing T-regs against auto-immune conditions: New cell therapies employ the polypharmacy arsenal of (typically immunosuppressive) T-regs to suppress mechanisms of inflammation and combat auto-immune indications. This rapidly burgeoning modality includes such players as Abata Therapeutics (TCR-Treg), Genti Bio (T-reg tuning), Mozart therapeutics (orchestrating T-reg networks), Sonoma Bio (for use against diabetes, Rheumatoid arthritis), and Quell Therapeutics (CAR-Treg).
• Exploiting our phagocytic macrophages: More novel approaches have scrutinized the therapeutic properties of macrophages, seeking to exploit its immune-stimulating effect and direct anti-tumor activity. Carisma Therapeutics (Car-M), Shoreline Biosciences (IPSC-derived M1), and Thunder Biotech (moto-CAR) are all developing candidates in this modality
• Leverage our oxygen carriers to stimulate broad immune response: Rubius Therapeutics is seeking to engineer red blood cells with immune-stimulating receptors (e.g., 4–1BBL and IL-15) to activate T-cell and NK cell activity against cancer, particularly to turn ‘cold tumors hot’. Despite a disappointing data read-out with its initial RTX-240 candidate, the company is seeking to continue with its RTX-224 option given encouraging preclinical data
• Transform our immune cells in vivo: As the next frontier, some companies are investigating in-situ re-engineering of cellular functions to combat disease, bypassing the need for ex-vivo manipulation or pre-conditioning regimens. The approach has attracted investor interest, seen by Interius Biotherapeutics’ $75M Series A and Umoja Biopharma’s $210M Series B.
• Apply cell therapy beyond oncology: Initial, highly positive results have come through for cell therapy applications in Type 1 Diabetes — Vertex’s potential cure via their engineered islet cells — and beta thalassemia — CRISPR Therapeutics’ induced transfusion-independence.

All the above approaches hold promise, but as before, preclinical results have yet to fully translate into clinical outcomes. Like the initially high prospects around off-the-shelf modalities, further clinical data is needed to truly assess this potential.

To recap, cell therapies still hold great promise to transform patient outcomes, yet it’s fair to say the initial buzz around the modality has wore off given the manufacturing (auto-CAR-T) and therapeutic (off-the-shelf) complexities that have followed. However, let’s not forget that for many patients with hematological malignancies, CAR-Ts have already offered incredible outcomes, nor ignore that researchers have continued to innovate in improving cellular therapeutics — advances which I will cover in my next post.

[Disclaimer: The views above represent my own, and not my current or previous employers. They reflect my understanding of the space, but may not be the latest, most comprehensive coverage of all companies, scientific advances, or clinical results.]