“In their murine tumor treatment studies, there was a dose response with one billion cells necessary for the best effects. How will this translate in the human setting? Will route of delivery affect the dose that is needed? These will all be important trial questions and endpoints,” said Yuman Fong, MD, surgical oncologist and director of the center for surgical innovation at City of Hope, Duarte, California.
Although immunotherapies are considered to generally come with fewer toxicities than conventional chemotherapies, the toxicities encountered can be unique and on occasion, surprising (eg, cytokine release syndrome3 and neurological side effects seen with chimeric antigen receptor T-cell [CAR-T] cells). Are there any likely toxicities with the new therapy that might be seen in the first human clinical trial?
“The question is whether an antigen-presenting cell, whatever the flavor, will present just the desired antigen or any antigen. If only the membrane associated antigen but none of the other RBC proteins were visible to T cells, it would be relatively low risk,” said Dr Ottensmeier.
No significant toxicities were reported in the preliminary mouse experiments, but the endpoints for the experiments were only between 40 and 55 days. Would any significant toxicities have been spotted during this time, then?
“RBCs can be susceptible to immune cell attack — the question is whether any residual proteins that are part of the normal makeup of the red cells could wind up being visible to the patient’s immune cells as a bystander effect,” Dr Ottensmeier noted, adding that it was unlikely that this would have been seen within the timescale of the preclinical work in mice.
“Infusing a large number of partly damaged RBCs along with immunoadjuvant and possibly checkpoint inhibitors bring worries of cross-reaction to red blood cell antigens and red cell lysis. Thus, vigilance for hemolytic anemia needs to be high,” said Dr Fong.
As with many experimental therapies, the first clinical trial is likely to include patients who have failed first-line therapies for their disease and may be heavily pretreated with conventional chemotherapies.
“We do think it will be a potential challenge that patients are pre-treated. The less pre-treated they are, the more likely that they will have a good immune status, but checkpoint inhibitors do work in patients treated with other treatments indicating that some of them will work,” said Dr Sharei.
As for the application of the RBC-based therapy, is the idea to isolate these from the donor or have a universal off-the-shelf approach?
“Ultimately, both an autologous format or allogenic format are on the table. One of the most exciting things about the SQZ technology as a universal platform is the simplicity at which it can be implemented to make sure that allogenic and autologous settings are feasible,” said Dr Sharei.