Contemporary CAR-T for Glioblastoma Induced ‘Dramatic’ Responses in Early Trial

— In three sufferers, one-time infusion of CARv3-TEAM-E T cells resulted in like a flash tumor regression

by
Mike Bassett, Workers Author, MedPage As of late
March 13, 2024

A current come to chimeric antigen receptor (CAR) T-cell remedy showed promise in treating recurrent glioblastoma, in accordance with a diminutive fraction I test.

Within the first-in-human trial, three sufferers with recurrent glioblastoma who were treated with CARv3-TEAM-E T cells experienced “dramatic and like a flash” tumor regression within days of receiving a single intraventricular infusion, reported Marcela Maus, MD, PhD, of Massachusetts Total Sanatorium and Harvard Scientific College in Boston, and colleagues.

“This test shows that antitumor CAR-mediated responses might perhaps also very smartly be without warning got in sufferers with glioblastoma, even in these with developed, intraparenchymal cerebral disease,” Maus and collaborators of the INCIPIENT test wrote in the Contemporary England Journal of Drugs.

The product uses CAR T cells engineered to focal point on the epidermal instruct enlighten receptor (EGFR) variant III (EGFRvIII) tumor-particular antigen, besides the wild-kind EGFR protein, thru secretion of a T-cell-participating antibody molecule (TEAM), the compare team explained.

On the opposite hand, “no subject the grand responses on this case assortment, we noticed eventual tumor development in two of the three contributors, which corresponded in fraction with diminutive persistence of CARv3-TEAM-E T cells over the weeks after infusion,” wrote Maus and co-authors. “As such, these files warrant future review of CARv3-TEAM-E T cells alongside systems particularly designed to attend sturdiness, perchance thru preconditioning with chemotherapy or extra scheduled infusions.”

While CAR T-cell remedy has demonstrated confirmed efficacy in blood cancers, its employ in stable tumors has been diminutive up to now, the authors pointed out.

Maus and colleagues in a earlier test developed CAR T cells to focal point on EGFRvIII, which is expressed in about 30% of glioblastomas. When that come had diminutive attain, they engineered the CAR T cells to teach TEAMs against wild-kind EGFR, which is now not expressed in traditional mind tissue nonetheless is virtually continuously expressed in glioblastoma.

Thus, this predominant-in-human, investigator-initiated, delivery-label INCIPIENT test became once designed to attend in thoughts this engineered T-cell product — CARv3-TEAM-E — in sufferers with recurrent or newly diagnosed glioblastoma.

The test enrolled the first three sufferers between March and July 2023. All had been treated with traditional-of-care radiation and temozolomide (Temodar) chemotherapy and entered the trial after disease recurrence.

One patient became once a 74-yr broken-down man who experienced disease recurrence at twelve months after diagnosis. On the first day after the infusion of the CAR-T product, imaging showed like a flash regression of the tumor that became once confirmed on imaging over the subsequent 2 weeks. On the opposite hand, that enchancment became once transient, and he went on to receive a 2d infusion of the CAR T cells on day 37.

Next became once a 57-yr-broken-down girl who enrolled in the test after imaging showed evidence of recurrent disease 6 months after diagnosis. An MRI scan on the fifth day after a single infusion of the CAR T cells showed attain total tumor regression. On the opposite hand, as with the first patient, the enchancment became once transient with evidence of recurrence displaying within 1 month after infusion.

The third patient became once a 72-yr man who showed evidence of development at 20 months after diagnosis and became once enrolled in the test in step with his EGFRvIII space at initiation diagnosis. On the 2d day after infusing the CAR T cells, imaging showed a lower in execrable-sectional dwelling of the tumor by 18.5%, which by day 69 had extra lowered by 60.7% from the preinfusion baseline charge. Unlike the moderately so a lot of two sufferers, this patient’s response remained sturdy on the closing review, greater than 150 days after a single infusion.

Adversarial events presumably attributable to the CAR T-cell infusion included grade 3 encephalopathy for 3 days in one patient, and grade 3 fatigue for 8 days in one other. All three sufferers experienced fevers and adjusted mental space after infusion.

“Our test of CARv3-TEAM-E T cells offers proof of precept that extra than one ground antigens might perhaps also very smartly be centered simultaneously with the employ of CAR T cells and confirms that EGFR is a lawful immunotherapeutic target in glioblastoma,” wrote Maus and co-authors. “Moreover, the secreted T-cell-participating antibody made by the CAR T cells became once safe no subject glossy expression of its target in systemic tissues.”