In Vivo CAR-T and B-Cell Depletion: Where to Next?
Autologous CAR-T has demonstrated incredible efficacy in both oncology and autoimmune disease, bringing a disease-modifying and even curative therapeutic options to patients. However, due to the laborious and costly procedure, only a subset of patients who could benefit ever receive the treatment. The promise of in vivo CAR-T is to scale this therapeutic concept by generating CAR-T cells directly inside the patient’s body. Billions of dollars of venture capital have been invested to realise this vision. The field is now starting to mature, and with the first clinical data readouts, we now understand far more about how this emerging therapeutic area will develop.
Here, we present our latest report, “In Vivo CAR-T and B-Cell Depletion: Where to Next?” which details the current state of the field, including our landscape of ~70 companies developing next-generation platforms.
Report Highlights:
● At least 14 companies have now entered the clinic. In broad terms, the field is bifurcated into integrating lentiviral platforms for oncology and transient LNP/RNA platforms for autoimmune disease.
● A second wave of earlier-stage platforms is emerging for oncology applications, based on non-viral, site-specific integration of CAR transgenes. Spearheaded by companies including Stylus Medicine and Addition Therapeutics, this approach aims to combine the safety and tolerability of non-viral delivery with the potency of genomic integration.
● Lentiviral platforms, such as Kelonia (acquired by Lilly for $7B), have reported impressive early clinical data. The safety profile of lentiviral vectors regarding off-target genomic integration looks promising based on emerging clinical and preclinical NHP data. Can the “second wave” companies compete with lentivirus if it proves to be largely safe?
● Platforms built on LNP-mediated delivery of transiently expressing mRNA look poorly positioned. With integrative platforms likely to dominate the oncology market, autoimmune disease is a natural fit. However, T-cell engagers (TCEs) have reported remarkable levels of deep B-cell depletion in NHPs and possess inherent advantages of manufacturability and scalability.
● Pharma is increasingly taking notice of this development, with the recent acquisitions of TCE developers Ouro by Gilead ($2.2B, $1.7B upfront) and Candid by UCB ($2.2B, $2.0B upfront).
● Even if TCEs eventually disappoint, in vivo CAR platforms with circular RNA payloads offer more potent and durable CAR expression compared to linear mRNA, and are likely to cause deeper B-cell depletion and higher efficacy with fewer and lower doses.
● A flurry of recent acquisitions with a combined deal value of >$15B over the last 18 months has left few late-stage companies standing and shrunk the pool of acquirers for those still developing platforms.
● At least 70 companies have not yet been acquired and continue to develop platforms.
Link to the report: https://docsend.com/view/49hrwgwnnrf7gfv7
