CTA:  Is that trafficking considered a difficult process, or has it proven difficult thus far?

Dr Levine: It’s no more difficult than what we have done in engineering CAR-T cells. The difficulty is in taking the theoretical approaches based on our immunologic knowledge and translating from in vitro and in vivo animal studies to humans and demonstrating what is effective. And those studies are ongoing now.

Another way I should mention with respect to solid tumors — there [are] beginning to be, over the past several years, some studies looking at not just intravenous injection, but intratumoral injection.

The group at City of Hope [in Duarte, California] and the group at Sloan Kettering [in New York, New York] have done preclinical studies; City of Hope did clinical studies on this.


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Going back several years, we have done intratumoral and intraperitoneal injections in a couple of patients in early studies with an antimesothelin CAR. This CAR was delivered to T cells via electroporation of RNA, and thus, induced only temporary expression on the T cell surface as a safe way to interrogate this new target.

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Direct injection may be an approach that you see in more clinical trials. Of course, it depends on the accessibility of the tumor, and would be limited. Let’s say there is a primary tumor or a primary lesion that is accessible, but there may be metastatic lesions that are not accessible.

So, one may deliver [the product] into that primary lesion, and either hope for T cells to leave that primary tumor through the circulation or to spread to the metastatic lesion.

There still may be limitations with the intratumoral injection. Additionally, consider the skill required for intratumoral injection and the comparability challenge when conducting multicenter clinical trials.

CTA:  Yes — what are the risks associated with in vivo versus ex vivo administration of CAR-T?

Dr Levine: So, I’m aware of the Sangamo trial in Hurler syndrome [Editor’s note: Sangamo Therapeutics is examining in vivo gene-editing approaches for the treatment of mucopolysaccharidosis I, or MPS I. Specifically, the company is studying investigational drug SB-318; ClinicalTrials.gov Identifier: NCT02702115]. I’m not a Hurler syndrome expert to know enough about the on-target and expected efficiency with delivery, but that always is a question with in vivo administration of a gene.

Secondly, what is the efficiency of delivery?  With the current expense of producing and testing viral vectors, any vector that does not hit target is a wasted expense.

With gene editing, there has to be enough efficiency in the target cell or the target organ and the absence of off-target effects, and that doesn’t even get at the issues with the CRISPR babies and editing embryos.