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January 6, 2022
Penn Spinout Verismo Therapeutics Trying to Skirt
T-Cell Exhaustion in Cell Therapy for Solid Cancer
NEW YORK – Around this time next year, University of Pennsylvania spinout Verismo Therapeutics hopes to launch a first-in-human clinical trial evaluating a new cell therapy dubbed "KIR-CAR."
Verismo's treatment isn't drastically different in design from the autologous CAR T-cell therapies that patients with hematologic cancers have benefited from, but it has a key twist meant to infiltrate solid tumors.
If the firm is able to file an investigational new drug application for KIR-CAR with the US Food and Drug Administration this year, the Phase I/II trial will launch at UPenn at the start of 2023 with the initial goal of enrolling 18 patients with advanced mesothelioma and mesothelin-expressing ovarian cancer. Verismo's primary goal in the trial will be to evaluate the therapy's safety and feasibility as well as patients' response rates, survival outcomes, and biomarkers of response.
According to Verismo CSO Laura Johnson, the company is confident it will be able to demonstrate KIR-CAR's safety and feasibility in the trial, because it employs the same targeting motif as CAR T-cell therapies that have already shown themselves safe in solid mesothelin-expressing tumors.
"This is a direct build on other works by Penn [researchers] that have been in the clinic and have shown results," Johnson said, explaining that researchers at the university have already conducted two mesothelin-targeting CAR T-cell therapy trials, in which the autologous, modified cells demonstrated safety and feasibility, albeit with limited efficacy.
"In those trials, they gave patients the [CAR T]-cells and saw a reasonable safety profile and some signal that they were working," Johnson explained. "The cells would make the appropriate cytokines in the patient, and you could watch the tumors shrink … but when [the Penn researchers] went back a month out, the cells were slim to none."
This is the challenging phenomenon that researchers, academic spinouts, and biotechs of all sizes have seen time and again with attempts to apply CAR T-cell therapy to solid cancers: The cells work in the short term, but fizzle out after that. The tumors often shrink while cells are therapeutically active and grow again as CAR T-cells dwindle and become exhausted.
Dodging terminal T-cell exhaustion
Verismo developed its approach, according to Johnson, by applying a clearer understanding of why CAR T-cell exhaustion takes place in the solid tumor setting. When "traditional" CAR T cells — that is, therapies developed similarly to those marketed for blood cancers — come into contact with solid tumors, they are often blocked from accessing the cancer cells thanks to a host of immunosuppressive elements. The first and most obvious immunosuppressive element is the fibrous outer physical barrier of the tumor itself.
"The cells often can't infiltrate the tumor in the first pass, so they have to come again and again and again, and keep seeking out all of these micrometastases long term," Johnson explained. In the process, a CAR T-cell's chimeric protein, which Johnson described as a "long, twisty rope," is "constantly wiggling on the surface [of the tumor]," and this constant and continued low-level T-cell activation is what ultimately exhausts the cells, rendering them unable to attack the cancer.
"Those cells seem to have a finite amount of activation they can go through, and if they're not able to fully rest down, they either die by committing cell suicide, or they become completely exhausted and don't work anymore," Johnson said.
The UPenn scientists with Verismo are not the only ones to recognize this terminal exhaustion as a key barrier to making CAR T cells work in solid tumors. Countless other firms have sprung up with plans to address the exhaustion with their own approaches, such as trying to reactivate exhausted cells by combining CAR T-cell therapy with immune checkpoint inhibitors.
What differentiates Verismo, according to the firm, is the novel way they've gone about addressing the exhaustion: by building the cells with a multi-chain structure that includes components found on natural killer cells.
"We use the same surface receptor that the CAR uses, an antibody fragment, and we tie that to an NK cell membrane anchor," Johnson explained. The killer immunoglobulin-like receptor (i.e., the "KIR"), which is the part found on an NK cell, differs in that it stays essentially dormant until it binds to its target, at which point it brings into play the accessory proteins — Verismo's is called DAP12 — to activate the T cell, recognize the tumor, and destroy it.
"It does absolutely everything a CAR T cell does," Johnson said of the KIR-CAR-based T cells, which Verismo calls "synKIR T cells." "It makes cytokines, it lyses the tumor, it puts out signals for other native immune cells to come into play. ... The difference is that it's almost a natural inducible system in that as soon as the tumor is eliminated, that receptor becomes free and the signaling stops."
When the signaling stops, the T cell can rest back down and recover so that it can reactivate the next time it encounters cancer cells. This way, the idea is, the cell therapy can avoid the terminal exhaustion state that has limited the activity of CAR T-cell therapies against solid tumors.
These modified, synKIR T cells have demonstrated in vivo that they can outlast traditional CAR T-cell therapies, avoiding exhaustion. In one mesothelioma solid tumor model, which UPenn researchers used for preclinical studies on the synKIR T-cell therapy, the traditional CAR T-cell therapy did not work, whereas the cells with the KIR-CARs eliminated all the tumors in the mouse models, including after long-term follow-up. The same occurred with in vivo glioblastoma models; using cells engineered with KIR-CARs designed to target EGFR, Johnson said, there was 90 percent survival and total elimination of the tumor.
Of course, preclinical models aren't fully predictive of how the cells will behave in human patients, but the preclinical work has Verismo's researchers "very, very excited," Johnson said, about the potential of synKIR T-cell therapy in the clinic.
Verismo has completed all the preclinical research it needs to file the IND for the mesothelin-targeting "synKIR-meso" therapy, Johnson said, and the firm has confidence moving it to the clinic.
'If it's not broken, don't fix it' vs. scaling up
Verismo's roots are closely tied to the development of the first commercial anti-CD19 CAR T-cell therapy approved for hematologic cancers, Novartis' tisagenlecleucel (Kymriah; tisa-cel). And as such, the firm is following the same tried and tested path for its product when it comes to clinical-stage production and manufacturing. The first-in-human trial is taking place at UPenn, and patients' harvested immune cells will be modified into synKIR T cells at the university's GMP cell therapy facility using a proven, albeit primarily manual, system.
Using manual manufacturing methods, currently marketed CAR T-cell therapies are largely limited to comprehensive cancer centers affiliated with major academic institutions, and often must be cryopreserved and shipped on either end of the manufacturing process to centralized facilities. The process can add days to the turnaround time that advanced cancer patients often don't have. Moreover, autologous CAR T-cell therapies are rarely administered in community oncology settings where the vast majority of cancer patients receive their care.
For a young spinout like Verismo, however, access to UPenn's facilities and cell manufacturing system, which have been used in countless CAR T-cell therapy trials, is invaluable. Johnson noted that in her experience, the vast majority of engineered cell immunotherapy studies have failed due to manufacturing challenges.
"People just don't have the experience really, in this new field, to know just how much is involved," Johnson said, explaining that for now, Verismo is going to use the "if it's not broken, we're not going to fix it" approach, and use the exact manufacturing protocol that has worked for what Johnson estimates to be many hundreds of UPenn CAR T-cell therapy trials. The only difference would be the KIR-CAR tweak in place of the CAR.
Should Verismo's therapy succeed in early studies and reach a point where the firm must scale up manufacturing, either for much larger clinical trials or commercial use down the line, Johnson said that the firm would consider looking toward new models to meet greater demand. Given the well-documented cost, logistical, and access barriers seen with marketed CAR T-cell therapies, a number of firms are considering automated manufacturing and innovative place-of-care models to try to ensure that more patients can access their cell therapies.
"We are very excited to see other companies that specialize in new manufacturing techniques and formulations and methodology, and we watch them very closely, because ideally we could potentially utilize that down the line," she said. "But for our first-in-human trials, we want to stay with what's been shown to work and what the FDA is comfortable with."
Verismo's risk-averse approach may be prudent in the short term, but down the line, if necessary, shifting from manual manufacturing processes to automation or novel systems is far easier said than done. This is partly because, for these bespoke therapies, the manufacturing process is an integral part of the treatment from a regulatory standpoint, and changing protocols from manual to automated systems can transform a therapy into what the FDA would consider to be an entirely different product.
Johnson said these concerns have been on her mind while working on the IND for synKIR-meso. "In some cases, if you even consider changing a reagent or a machine, it can be considered a completely different drug product," she acknowledged.
Still, for now, Verismo has confidence that bridging trials, coupled with the firm's collective years of cell therapy expertise will allow it to navigate the relatively new and evolving regulatory landscape for cell therapies. Johnson herself worked previously in Steven Rosenberg's lab at the National Cancer Institute, and CAR T-cell therapy pioneer Carl June is the firm's founding adviser.
"As long as you stick to biologic basics, logic, and common sense, and do things in a [good laboratory practice] manner, the FDA seems to be very agreeable," Johnson said. "I'm not concerned."