News media reports suggest John McCain has been diagnosed with(GBM), a relatively rare but quite deadly cancer estimated to affect ~200000 people in the US each year. This answer focuses on anti-GBM CAR-T cell immunotherapies, most of which are in early experimental stages with at least one report of complete remission. This is notable considering median survival after primary GBM diagnosis is usually a mere ~15 months ( ).
No doubt the best GBM immunotherapy specialists would likely be consulting on McCain’s case. CAR-T, an approach that hadn’t matured in 2008 to the extent it has in 2017, is certainly advanced enough that they may well try it. However, at the moment, there’s no guarantee it will cause remission and/or cure. 2008 because that’s when Ted Kennedy was diagnosed with the same/similar cancer, dying some 15 months later.
What is CAR-T?
The CAR-T approach is a T cell immunotherapy currently being intensively studied against GBM as well. In this therapy, T cells, usually mostly CD8, isolated from the patient’s own blood, are genetically engineered to express an antibody-derived molecule on their cell surface. In its simplest iteration, this engineered molecule typically consists of an antibody’s single chain variable fragment (scFv) fused to the transmembrane and cytoplasmic (signaling) portions of a T cell-specific molecule called CD3. Hence the name CAR-T or Chimeric Antigen Receptor-T cell. Such a genetically engineered CAR molecule usually specifically binds a cell-surface molecule expressed by the tumor. Such specific binding in turn activates the genetically engineered CAR-T cells, some of which then seem to succeed in killing tumor cells.
Early attempts to try CAR-T for GBM, especially recurrent ones, were considered a lost cause for a largely technical reason. GBM typically grows rather aggressively while taking out the patient’s own T cells, culturing them in vitro to expand and stimulate them in multiple rounds of cultures to finally yield a customized therapeutic product typically used to take >3 to 4 months. More recent approaches have shaved this process down to a matter of < 2 weeks, making this approach far more realistic and feasible (). Caveat is stimulation approaches to expedite the process could also increase scope for non-specific immune responses, i.e., collateral damage.
TSA (Tumor-Specific Antigen) versus TAA (Tumor-Associated Antigen) as cancer immunotherapy targets for GBM
Key question at this stage then is what should the antibody portion of an anti-GBM CAR target? Does GBM express unique cell surface molecules that could serve as specific targets for CAR-T cells? An ideal target molecule would be solely expressed by the tumor, i.e., TSA (Tumor-Specific Antigen).
Problem is too few validated TSAs have been identified so far for tumors in general with none reported thus far for GBM. On the contrary, at least one study suggests GBM appears to have low mutational burden and few neoantigens (TSAs) (). If lack of TSAs indeed turns out to be a hallmark of GBMs, successful immunotherapies, especially CAR-Ts will be more difficult to realize.
Choice then falls to the next best option, target molecules (antigens) over-expressed by tumors, i.e., TAA (Tumor-Associated Antigens). Current anti-GBM CAR-T immunotherapy thus relies on targeting TAAs. Since TAAs are expressed by normal tissue cells as well, albeit hopefully at much lower levels, higher risk of collateral damage in the form of ‘on-target-off-tumor’ effects is a major problem with using TAA targets in cancer immunotherapies such as CAR-Ts.
Is CAR-T feasible against GBM? TAA targets being tested in anti-GBM CAR-Ts
IL-13 receptor alpha 2 (IL-13Ra2)
One of the earliest anti-GBM CAR-T approaches took advantage of the observation that many, though not all, GBM over-express IL-13Ra2 () ( ), a high-affinity receptor for the cytokine (IL-13). Such over-expression correlates with poor prognosis ( , ).
IL-13Ra2 is also not an ideal target since it is highly expressed by normal testis tissue (7), i.e., high risk for ‘on-target-off-tumor’ effects in men.
Nevertheless, a small anti-GBM CAR-T pilot study () published the first-in-human intracranial IL-13Ra2-specific CAR-T cell pilot study of 3 GBM patients ( ) showed
- Manageable side-effects.
- Quantifiable immune responses against their tumor (in 2 of 3).
- Reduced tumor expression of IL-13Ra2.
These three patients survived >8 to >13 months post-relapse, i.e., appreciably longer than most GBM patients with recurrent disease.
Longer term follow-up of one of these 3 patients provided one remarkable proof-of-concept result (). Fifty years old at the time of the original study, this patient’s GBM had proven resistant to surgery (resection), radiation and a chemotherapy drug, temozolomide. Since this patient developed additional spinal cord lesions as well, the researchers decided to intra-cranially infuse the IL-13Ra2 CAR-Ts not just in one but two locations.
Not only did the intracranial and spinal tumors regress, importantly without serious side-effects, but the patient was reported to be alive as recently as Feb 2017 (10), presumably several years from their primary diagnosis. Even with the most state of the art standard of care, GBM prognosis is usually still rather bleak so such a result in even one patient was considered worthy enough for publication in a top medical journal.
Epidermal Growth Factor Receptor variant III (EGFRvIII)
Another cell-surface molecule, the(EGFR) variant III is a mutated form of EGFR frequently found upregulated in ~25 to 35% of GBM patients ( ). GBM patients with EGFRvIII-positive tumors also tend to have the shortest survival (12).
Plenty of mouse model studies data suggest EGFRvIII would be an effective CAR-T target. Problem is such preclinical models are notoriously poor in predicting human outcomes. Nevertheless, several pilot studies are ongoing (, , , ), both in the US (NCI, UPenn, Duke) as well as China (Beijing Sanbo Brain Hospital), to assess first the safety (what’s a safe number of EGFRvIII CAR-T cells to infuse, how) and then efficacy. These trials are ongoing and no results have yet been published at this time (Aug, 2017, see tale below from ).
One published study (18) on 10 patients with recurrent GBM showed EGFRvIII CAR-T was both feasible and safe but without appreciable clinical benefit, something the authors attribute to a recognized tendency for strong immune response-inhibiting GBM tumor environment. They conclude EGFRvIII CAR-T would work better combined with immune checkpoint inhibitors.
Her2 is a well-known TAA, being commonly over-expressed in breast cancers. Also over-expressed in some GBMs made it a logical choice of target for anti-GBM CAR-Ts as well with at least two ongoing pilot studies (, , see table below from ) though no results have been published yet.
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