ESMO: BioNTech's new CAR-T manufacturing process boosts potency … and side effects

MADRID—BioNTech’s new manufacturing process for CAR-T seems to have done the trick in boosting the potency of the solid tumor therapy BNT211, but that bit of extra juice appears to have upped the side effect profile as well.

The famed mRNA company has some dosing changes in mind that could help bring down the rates of cytokine release syndrome (CRS) seen in an ongoing early-stage trial. And according to Benjamin Rengstl, director of clinical development and immunoreceptor therapy, the data shows that CAR-T can indeed work in solid tumors.

At the European Society for Medical Oncology Congress, BioNTech detailed signs of clinical activity with BNT211 and a persistence of CAR-T cells when combined with CARVac, the biotech’s RNA vaccine that’s designed to boost efficacy of the CAR-T cells. BNT211 targets the antigen Claudin-6 (CLDN6), which occurs in many solid tumors including ovarian cancer, sarcoma, testicular cancer, endometrial cancer and gastric cancer. The trial tested four dose levels with BNT211 alone or with CARVac.

An overall response rate of 45% was seen in 38 of the 44 evaluable patients, plus a disease control rate of 74%.

“Now finally, we can answer the question that we really do see a difference … in the [pharmacokinetics] of the CAR-T cells, so they persist way longer,” Rengstl told Fierce Biotech on the sidelines of the conference in Madrid. “I have to say the new product is really more potent but also a bit more toxic.”

Of 27 patients who received dose level two with or without CARVac, 13 experienced partial responses with an ORR of 59% and a disease control rate of 95%. These patients also showed a prolonged persistence of the CAR-T cells.

“So this means that basically every patient is benefiting. There was a single patient out of … 24 not responding to the treatment,” Rengstl said.

BioNTech changed the manufacturing process after providing a peak at BNT211 during last year’s ESMO Congress. The new data cut features a more automated manufacturing process that is more robust, scalable and creates a more potent product.

BioNTech then conducted a new dose escalation process, presenting a very early look at the American Society for Clinical Oncology meeting in June. At ESMO, more follow-up data is available to begin to fill in the efficacy and safety picture.

Of the 44 total patients, there were 23 cases of CRS, a known complication of CAR-T therapy where the immune system overreacts to a drug and causes fever, nausea and other symptoms that can become serious. BioNTech said these adverse events were “dose-dependent.” Most of the events were grades 1 and 2, representing less serious cases, but there was one grade 3 and a grade 4.

The patient with the grade 4 CRS case experienced acute respiratory distress syndrome and spent “quite a while” in intensive care but has since recovered. Rengstl said the person remains on treatment and is still benefiting about a half year later. This person was the only patient to receive the highest dose allowed under the trial protocol, which BioNTech has since backed off from.

BioNTech is zeroing in on the second dose level, which is showing efficacy without the safety challenges. Rengstl believes the toxicities can be managed at this level.

“The issue is that basically we are pioneering in the field of solid tumors. So there's not much data out there. All that we know about classic CAR-T cells is coming from [hematology] indications and you cannot really translate this,” Rengstl said.

One positive sign in the safety data is that there were low levels of neurotoxicity with just mild cases reported, he pointed out. There were, however, liver toxicities that did not occur with BioNTech’s previous product that was created using the previous manufacturing process. Rengstl said this is likely because the new process creates more cytokines, which are activating the endogenous immune system and organs like the liver.

“We are still in the phase of figuring out what is going on there, but we are confident that with certain measures we can mitigate those side effects,” he said.

BioNTech still doesn’t know about the durability of BNT211. That’s something the company will need to prove to make a real change on the CAR-T scene, where relapse has been common. It’s a known issue that patients typically relapse on CAR-T after a certain point, but Rengstl believes the early data that include CARVac show some promise on this issue.

“We also have treated patients with redosing and could show that they can respond again, so we are quite confident that we will see it, finally, not only on the PK level, the contribution of the vaccine,” he said.

Another challenge for the BNT211 program is simply being first. Rengstl said BioNTech is working with European regulators now to negotiate a single-arm trial for future studies instead of a randomized one as requested. There's just too much risk for patients with germline tumors, who are all typically very young with testicular cancer, he said. 

"We are, at the moment, pushing back a bit," Rengstl said. "The comparator that authorities might want to have is palliative care. So for me this makes no sense to compare a potential curative approach with one that prolongs life—not really, because they have a median survival of three to four months."

BioNTech will need to sort out the safety and regulatory issues, but the company has put up efficacy to show that CAR-T could have a future beyond blood cancers. The next steps are to start the phase 2 portion of the trial, which will focus on germ cell cancers, in the EU and U.S., where Rengstl says there are still discussions going on. 

"The EMA is the authority that we are talking most with and now with the data that we're presenting later today, there is more to discuss, more indications and more trials," he said.

Rengstl said that patients have reported an improved quality of life compared to previous chemotherapy: “So often we get the information that patients didn't come to the visit, but sent greetings from vacation.” 

To read more of Fierce Biotech's coverage of the ESMO Congress, click here. Fierce Pharma's coverage is available here.