 Juan Carlos Lopez |
 Andy Marshall |
Just over a week ago, AbbVie paid $2.1 billion for Capstan Therapeutics’ in vivo anti-CD19 chimeric antigen receptor (CAR)-T cell therapy (CPTX2309) for B cell-mediated autoimmune disorders, which is currently in phase 1 testing. In the past few days, EsoBiotec (acquired by AstraZeneca earlier in the year) also published its first clinical data on a lentiviral-delivered anti-B-cell maturation antigen (BCMA) CAR-T approach (ESO-T01) for multiple myeloma, detailing responses in four patients, two of whom showed complete remission. With a host of other companies working on in vivo delivery into endogenous T cells—including Interius BioTherapeutics, Umoja Biopharma, and Orna Therapeutics, the field of in vivo delivered CAR-T cells appears poised at a tipping point.
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Since transforming the face of cancer treatment in 2017, autologous CAR-T cell therapy has been dogged by logistical issues that have limited commercial rollout and increased costs—the need for leukapheresis, laborious cell harvesting, heterogeneous cell expansion, lengthy turnaround times, and inconsistency of batches—with access limited to just a few clinical centers. Extensive waiting lists can mean many patients die before even being treated, which has driven the search for ex vivo approaches that shorten manufacturing times using fully closed systems and/or miniaturization. Given these challenges, delivery of a CAR-encoding mRNA to a T cell in vivo could be a game-changing technology: No need for viral vectors; no leukapheresis/chemo; no ex vivo manipulation, no requirement for multiple patient hospital visits; no convoluted training of personnel; and no risk of second primary T-cell cancers due to insertional mutagenesis. This last issue has loomed over the field, with all CAR-T therapies carrying black box warnings, although at the end of June the FDA removed all requirements for Risk Evaluation and Mitigation Strategies (REMS).
Writing in Science, the founding team of Capstan Therapeutics, headed by Carl June and Bruce Levine at the University of Pennsylvania and Haig Aghajanian of Capstan, report proof of concept data that functional CAR T cells with antitumor activity can be produced in animal models without any ex vivo manipulation. A key breakthrough in their effort was the development of lipid nanoparticles (LNPs) specifically designed to target T cells and to overcome the propensity of LNPs to accumulate in the liver. To avoid this problem, the authors screened a set of ionizable lipids to identify L829, a lipid that incorporates a tertiary amine headgroup that reduces non-specific interactions with the hepatic system due to its pH-dependent protonation and neutral charge. Ester cleavage sites in the lipid also promote rapid breakdown in, and clearance from, hepatocytes. A final step was to decorate L829 LNPs with a mAb targeting CD5, a T-cell specific marker. The resulting LNP showed limited liver uptake in rodents and non-human primates compared with control LNPs.
To test the potential of L829-containing LNPs to generate functional CAR-T cells, the team engineered them to incorporate 1) mRNA encoding a CAR that binds CD19 on B cells and 2) an antibody targeting CD8+ T cells. These CD8-L829-CD19 targeted (t)LNPs successfully delivered the mRNA in vitro to CD8+ T cells from healthy subjects and from people with B cell-mediated autoimmune diseases. In vivo, these CAR T cells had anti-tumor activity in a humanized mouse model of B cell acute lymphoblastic leukemia.
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In cynomolgus monkeys that received repeated doses of CD8-L829 tLNPs containing anti-CD20 CAR mRNA (instead of anti-CD19, which is not cross-reactive between human and monkey), sustained B-cell depletion was observed that lasted for one month. Importantly, reconstituted B cells were predominantly naïve, implying an immune reset — a key therapeutic goal in autoimmunity.
The Capstan in vivo mRNA-encoded CAR T platform eliminates the need for ex vivo manipulation and lymphodepleting conditioning. It avoids the risks often associated with the use of viral vectors that integrate into the genome. It also is transient, allowing dosages to be optimized and quickly stopped if patients suffer adverse events associated with neurotoxicity or cytokine-release syndrome. It will be interesting to see whether the approach is scalable and whether it can open up conditions where long-term CAR-T cell persistence might not be necessary, such as autoimmune disease.
Going forward, an important question will be to determine the potential immunogenicity of the tLNP formulation (especially as the mRNA treatment may be given multiple times), and whether tLNPs cause elevations of human liver enzymes like alanine transaminase or aspartate aminotransferase. Liver toxicity of a novel liposome formulation already caused a clinical hold for Verve Therapeutics’ base editing therapy last year. Future work will also need to define optimal dosing, durability, and long-term safety of this approach. But the work of June, Aghajanian and their colleagues is a compelling advance promising a new era of widely available adoptive T-cell therapies for B-cell driven hematological cancers and autoimmune conditions. A single dose of any of the seven currently approved commercial ex vivo CAR-T therapies costs ~$500,000. A vial of an in vivo treatment is likely to cost an order of magnitude less.
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