“The whole idea of this technology causing other genetic damage is something we need to look out for; there’s only a small number of patients with end-stage malignancies in this initial trial, [so] caution is still needed to determine the long-term effects of gene manipulation in this context,” said Dr Maloney.

Given the multiple-step processing of the cells, how scalable is the technology should it be proven in larger human trials?

“At this point, the method of adapting cells isn’t practical; this was an academic pilot study,” replied Dr June.


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The T cells were constructed with now-outdated technology and there were also several stages of cell manipulation with good manufacturing practice (GMP) requirements. The FDA also insisted on a month-long culture of the cells after they were modified to monitor for transformation.

“I think it’s very likely that the technology will be able to be scaled very easily,” said Dr Maloney. “The real question is, will these kinds of peptide-directed T cells ever be able to cause effective antitumor activity in the bulk of these cancers that these cells are trying to address?”

Dr June and his team are now editing CAR-T cells to try and improve their efficacy and will start with those targeting CD19, a B-cell–specific surface protein which is commonly used as a target of CAR-T in hematological malignancies. He hopes the trial will be recruiting by the end of the year.

“We have first base and can now move forward to detect efficacy. Using more modern regents, more specific Cas9, and better guide RNAs, we will hopefully be able to treat with more doses of cells and higher levels, and see if it enhances responses over CAR-T cells which are not genetically edited,” said Dr June, adding that he also hopes gene editing could help with the T-cell exhaustion often seen with CAR-T.

Although the number of patients in this initial trial was incredibly small and the responses were less than groundbreaking, many are hailing this as an important historical step in the use of CRISPR-Cas9 in cancer therapeutics. However, experts are warning that this is just the start of trying to increase the efficacy of CAR-T in solid tumors.

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“As they are now, CAR T-cells cannot on their own eradicate solid tumors; we need to think [about] other ways to make this possible. Engineered T cells enter an environment where there can be hypoxia, pH differences, other cells attacking them — it’s like a warzone; we have to make the T cells as good as possible, but also consider all of these factors,” said Dr Klampatsa.

CAR-T has shown impressive results in a subset of hematological cancers that have often failed first-line therapies, but have yet to provide significant clinical benefit to large numbers of patients.

“We cannot move to huge trials unless we see this therapy has a chance of really helping people with solid tumors. At the moment, with cell-based therapies, there are trials in progress. But when it comes to using them on a wider patient population, making them more mainstream, we need to show better clinical benefit and efficacy of these therapies,” said Dr Klampatsa.

References

  1. Stadtmauer EA, Fraietta JA, Davis MM, et al. CRISPR-engineered T cells in patients with refractory cancer. Science. 2020;367(6481):eaba7365.
  2. Schietinger A, Greenberg PD. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 2014;35(2):51-60.