AACR 2019 – Baylor sets the benchmark for Bellicum

A Baylor College study suggests to investors what Bellicum’s upcoming first-in-human trial of BPX-603 will have to match.

Conferences

Given the extent to which the market has fallen out of love with Bellicum over the past two years it is important for the CAR-T company to have a good AACR meeting. On the basis of two academic studies, highlighted at today’s AACR press conference, the omens are good although there are still doubts.

The most relevant study presentation details the Baylor College autologous Her2-targeting CAR on which Bellicum’s next clinical asset, BPX-603, is based; given the history of this antigen the most notable feature of the data is that Baylor’s construct appears safe. On the other hand, a separate trial yet again calls into question Bellicum’s IP.

It was only last month that Bellicum disclosed that BPX-603’s target was Her2, though sharp-eyed investors will have noticed that the company had been looking at this antigen for a while. Either way, Her2 seems an unusual choice, given its expression on healthy as well as cancerous cells, and the notoriety of an NCI trial of a Her2-directed CAR that caused a patient death.

Judging by Baylor’s AACR presentation, however, toxicity might be controllable. Dr Shoba Navai, presenting the data, said she had treated 11 subjects with Baylor’s so-called HER2-CAR T cells, and while there were nine cases of cytokine release syndrome none exceeded grade 2 in severity.

Repeat dosing

Dr Navai’s study, in Her2-positive sarcoma patients, involved repeated dosing of the CAR-T cells – an idea that is becoming increasingly popular, though one that relies on sufficient cells being generated from a single apheresis to avoid multiplying the costs of what is already a very expensive procedure.

Repeat dosing could also enable a CAR with poor persistence to be given, thus reducing the risk of toxicity while maintaining overall efficacy.

Subjects in the Baylor study received up to three CAR-T infusions with lymphodepleting chemo, and those who responded were given up to five more cycles without lymphodepletion. All were extremely late-stage, having failed up to five salvage therapies.

Dr Navai reported two complete remissions. And there was a key finding that underpinned the repeat dosing approach: one of the responders relapsed after 18 months, but on retreatment with HER2-CAR went into a second complete response that has now been maintained for a further 15 months.

No doubt Bellicum will pay close attention to these data as it designs BPX-603’s first-in-human study, due to begin this year. BPX-603 employs a similar construct to HER2-CAR, except for its use of a humanised binder (HER2-CAR’s binder is murine) and dual “on” and “off” switch domains.

Selected Her2-directed CAR-T therapies
Sponsor Project Cancer types Trial ID
Mustang Bio/NCI MB-103 Brain or leptomeningeal metastases NCT03696030
Baylor College HER2-CAR 18% ORR in Her2 +ve sarcoma (repeat dosing) NCT00902044
Baylor College HER2-CAR Her2 +ve CNS tumors NCT02442297
Seattle Children's Hospital HER2-specific CAR Her2 +ve CNS tumors NCT03500991
Leucid Bio/King's College  T1E28z* Head & neck cancer NCT01818323
NCI Anti-Her-2 cells Colon cancer NCT00924287**
Bellicum BPX-603 Gastric & endometrial cancers TBA
Source: clinicaltrials.gov; *targets Erb dimers including Her2; **study terminated owing to patient death.

The switch technology has been a sore point for Bellicum. It was initially a unique selling point, but subsequently had its utility in serious and sudden toxicities questioned, before it finally became apparent that Bellicum did not have exclusive rights to it.

Investors were again reminded of this through the second CAR-T study highlighted by AACR today, comprising Memorial Sloan-Kettering’s mesothelin-targeting asset IcasM28z. This, it was stressed, includes an Icaspase-9 switch that can be activated “in case of an unexpected toxicity”.

This same switch, of course, has long been described by Bellicum as “proprietary”; the company has previously said that it permits limited use of the technology by academics, and this appears to be what is going on in the Memorial study. However, Poseida is one commercial entity that is blatantly using the same switch.

It is not clear how long IcasM28z will stay in academic hands, either. The Memorial team involved, including Dr Michel Sadelain, has a tie-up with Atara over a mesothelin-targeting CAR that the company is taking forward as ATA2271; however, this uses a different co-stimulatory domain from that employed by IcasM28z, and does not appear to use a safety switch.

In general targeting mesothelin has proved a non-starter, as first highlighted at the AACR conference four years ago. The Memorial data suggest a path forward in terms of combatting T cell exhaustion: 14 of 19 mesothelioma subjects given IcasM28z were put on checkpoint blockade, resulting in two complete and five partial remissions.

The UK-listed company Maxcyte is also developing an anti-mesothelin CAR, MCY-M11.

For Bellicum, the most important thing right now is to get the Her2-directed trial under way; an 18% overall response rate might not seem like much, but if BPX-603 can match it safely the company could have something to celebrate at last.

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