Someone in my Twitter stream kindly shared a link to an article this morning on how removing the PD-1 brake enhances the effect of chimeric antigen receptor (CAR) T cells in solid tumour models.

Whoa!  Read that again and digest the implications.

We already know that the current leading immunotherapies, blocking PD-1/PD-L1 and adoptive therapy with CART, are rather effective in some cancers, but I’m willing to bet that few would have expected this effect, even though it makes a lot of sense when you actually sit down and think about it.

Certainly it gave me goosebumps reading the articles.

What do the papers show?

Morales-Kastresana et al., (2013) offer a nice review of the state of play with immunotherapies that is well worth reading. They explain that,

“It is conceivable that PD-1 limits the signal transduction capabilities of the artificial chimeric receptors at the immune synapses between CAR-transduced cells and tumor cells. The tumor cell lines in culture constitutively expressed PD-L1 and presumably keep expressing this molecule in the tumor microenvironment.”

Much of the work with CART to date has been reported in CLL and ALL from Carl June’s lab at U. Penn, but what about the potential in solid tumours? Ovarian and breast cancers have been mentioned as possibilities from thought leaders I’ve spoken to at recent conferences, although we’ve been waiting to see some solid preclinical data that might help understand the best options with this approach.

Morales-Kastresana and colleagues describe the important work of John et al., (2013) as:

“A combination of T cells with a CAR recognizing HER-2 on the surface of tumor cells and a mouse anti-PD-1 mAb in the treatment of HER-2 breast carcinoma–transplanted tumors. The CAR chosen includes the signaling domains of CD28 and CD3z. Each of the elements in the two-pronged combination shows signs of monotherapy efficacy, but there are very interesting signs of synergistic, rather than additive, effects on the HER-2–transfected mouse models.”

Although this is preclinical work, the Australian group have demonstrated something very simple and elegant – namely, uncoupling the PD-1 brake can make CART more effective in two solid tumour HER2 breast cancer models:

“This combination therapy was shown to significantly inhibit tumor growth in two different mouse models leading to eradication of disease in a proportion of mice. Both of these approaches have been used singly in the clinic showing good safety profiles where objective and complete responses have been reported against various cancer types.”

They also went on to observe that:

“However, many patients do not respond to either treatment alone. The current study shows that combining these two modalities can dramatically increase antitumor effects against established disease. Furthermore, we show that the increased effects from combination therapy did not cause pathology in mice and that therapeutic responses strongly correlated with a decrease in MDSCs.”

Where MDSCs are myeloid-derived suppressor cells.

Myeloid cells, for the uninitiated, are often associated with inflammation. Reducing them is a very good thing in cancer therapeutics.

Oddly by coincidence, I was reading an excellent article on combining anti-PD-1 and CTLA-4 in PNAS from James Allison’s lab yesterday (see References below) where they also demonstrated that a reduction of myeloid cells in tumours following anti-PD-1 therapy.

What does this research mean?

This is the first time I’ve seen evidence that blocking PD-1 can potently enhance CAR T-cell therapy. It clearly has significant scientific and clinical implications for potentially improving therapeutic outcomes of this approach in patients with cancer, including solid tumours.

These are promising preclinical results in mouse models but we should be very careful making any leap or extrapolation to clinical trials or outcomes in humans at this stage.

There are also many potential challenges ahead.  Not least is the complication of cross company R&D.

Novartis and Celgene are the leaders in developing CART therapies, while several companies including BMS, Merck, Roche, AstraZeneca and others are advancing anti-PD1 or PD-L1 immunotherapies in their R&D pipelines. As far as I know, no one company has both approaches in house, so this will mean alliances would need to be developed in order to progress the exciting concept. I really hope it happens, but commercially, two company combination trials and alliances are still very challenging for the Pharma industry on many levels.

It is sometimes easier to license in an additional compound than it is to try and work out a two company clinical trial, strange though that may seem to industry outsiders.

Update: (17 February 2014)

This morning Novartis announced that they had acquired Co-Stim Pharmaceuticals, a Cambridge, MA based antibody company that develops immune stimulants and checkpoint inhibitors, including anti-PD-1.  Although the compounds are currently in Discovery phase, we can expect Novartis and NIBR to be focusing significant effort on moving some of these agents through preclinical then to the clinic reasonably speedily.  The potential for combining a PD-1, not only with the CAR- T cell construct, but also with existing TKIs in various solid tumours offers a wonderful opportunity to explore the broader environs of cancer immunotherapy.

Nice job!


ResearchBlogging.orgJohn LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, & Darcy PK (2013). Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells. Clinical cancer research:  PMID: 23873688

Morales-Kastresana A, Labiano S, Quetglas JI, & Melero I (2013). Better performance of CARs deprived of the PD-1 brake. Clinical cancer research: 19 (20), 5546-8 PMID: 24004672

Curran MA, Montalvo W, Yagita H, & Allison JP (2010). PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of Sciences of the United States of America, 107 (9), 4275-80 PMID: 20160101