Update on Mayo Clinic stem cell therapy trial

Posted by Ethan Perlstein in Research News on December 11, 2019 # Research, Clinical Trials

Trauma-related spinal cord injuryOn the Wednesday before Thanksgiving two weeks ago, Will Reeve presented a story on Good Morning America about an individual with a spinal cord injury who was the first patient to receive autologous (his own) adipose-tissue-derived (belly fat) mesenchymal stem cells delivered via intrathecal (spinal tap) administration in the now two-year-old CELLTOP clinical study, directed by Dr. Mohamed Bydon at the Mayo Clinic in Rochester Minnesota.

This story received a lot of buzz given GMA’s platform and because it was reported by Will Reeve, the youngest of the three Reeve children who are all working tirelessly for the cause of SCI as Reeve Foundation Board members and patient advocates. On the same day the GMA piece aired, an n-of-1 case report appeared in Mayo Clinic Proceedings (hereafter Bydon et al.) telling the story of the first patient to receive a stem cell infusion. As described in the case report, he sustained a high cervical injury (C3-4), was diagnosed as ASIA A, and as is often the case post-injury, he experienced spontaneous recovery followed by plateau at six months at which point he was deemed ASIA C (although according to clinicaltrials.gov that should have excluded him from the study).

After scrutinizing Bydon et al. and its cited literature, I would like to put on the record qualifications and caveats so that the SCI community can understand more about this study and then decide for themselves if his outcomes post-intervention are relevant to them and their unique injuries. One fact to point out right away – and I know the first question on the minds of the vast majority of people living with a chronic injury: the CELLTOP trial excludes any person living with SCI for longer than one year, i.e., acute and sub-acute patients only.

Next, it is critical to assess the baseline of the individual profiled. It’s important to note that the patient in question was already slowly walking (635 ft for 12.8 minutes at a pace of 0.25 m/s) when he received the stem cell infusion, so concerns about cherry-picking a responder or super-responder even over a non-responder are valid.

In the discussion section, Bydon et al. describes a 2016 study involving 14 Korean patients living with SCI who received adipose-derived mesenchymal stem cells (AD-MSCs) using a similar protocol, as follows:

“Hur et al21 reported the first human trial of intrathecal autologous AD-MSCs (dose, 90 million cells) in 14 patients with SCI, 12 of whom were reported to have ASIA grade A neurologic impairment at baseline. The authors reported improvement in motor function in 5 patients.”

When you actually read Hur et al. to understand how much improvement those five patients experienced, the motor improvements are modest and consistent with the small effect sizes reported in other AD-MSCs trials for SCI. On the other hand, it’s noteworthy that sensory improvements were observed in 10 out of 14 patients as far out as eight months post-infusion – though one patient experienced sustained sensory decline as early as one-month post-infusion. Here are Tables 2 & 4 reproduced from Hur et al. (keeping in mind that the ASIA motor and sensory score scales go from 0 to 100):

Table 2
AISA motor scores


baseline

1M

2M

4M

6M

8M

Patient 1*

50

52

54

54

56

56

Patient 2

50

50

50

50

50

50

Patient 3*

73

76

77

77

77

77

Patient 4

50

50

50

50

50

50

Patient 5

38

38

38

38

38

38

Patient 6

50

50

50

50

50

50

Patient 7

50

50

50

50

50

50

Patient 8

72

73

72

72

72

72

Patient 9*

0

0

0

0

1

1

Patient 10

50

50

50

50

50

50

Patient 11*

40

40

44

44

44

44

Patient 12*

26

27

30

30

30

30

Patient 13

50

50

50

50

50

50

Patient 14

10

10

10

10

10

10

Table 4
ASIA sensory scores



baseline

1M

2M

4M

6M

8M

Patient 1*

pin prick

78

78

80

94

96

96


light touch

78

78

80

94

96

96

Patient 2

pin prick

78

78

78

78

78

78


light touch

78

78

78

78

78

78

Patient 3

pin prick

112

112

112

112

112

112


light touch

112

112

112

112

112

112

Patient 4*

pin prick

86

94

94

94

94

94


light touch

86

94

94

94

94

94

Patient 5*

pin prick

28

28

28

32

32

32


light touch

28

28

28

32

32

32

Patient 6

pin prick

88

78

78

78

78

78


light touch

88

78

78

78

78

78

Patient 7*

pin prick

70

70

70

70

70

72


light touch

70

70

70

70

70

72

Patient 8*

pin prick

86

90

90

90

90

90


light touch

86

90

90

90

90

90

Patient 9*

pin prick

8

8

18

18

20

20


light touch

8

8

18

18

20

20

Patient 10*

pin prick

64

70

70

70

70

70


light touch

64

70

70

70

70

70

Patient 11*

pin prick

40

46

76

76

76

76


light touch

70

70

76

76

76

76

Patient 12*

pin prick

22

26

32

32

32

32


light touch

22

26

32

32

32

32

Patient 13

pin prick

44

44

44

44

44

44


light touch

44

44

44

44

44

44

Patient 14*

pin prick

51

53

53

53

53

53



51

53

53

53

53

53

On the plus side, Hur et al. and Bydon et al. don’t report any safety concerns or adverse events during the study period. It’s important to note that neuromas (spinal tumors) have been observed in other stem cell trials, so we should always view it as a possibility in SCI and take proper precautions. All it takes is one rogue cell eluding the immune system.

Now I don’t mean to single out Bydon et al., especially because it’s just an n-of-1 case report. Yet, given the outsized press coverage, the SCI community deserves a critical reading of this or any study, whether it’s about a potential stem cell or any other treatment modality. There will almost certainly be a role for stem cell grafts in addressing the site of injury and likely part of a combinatorial SCI intervention cocktail.

And while I believe the SCI community should absolutely embrace n-of-1, it’s important to contextualize each patient. What is their baseline at study enrollment? How can we be sure to rule out spontaneous recovery? Is there anything that can be learned about responders versus non-responders versus super-responders? I hope the CELLTOP study publishes on the entire trial cohort of 10 patients soon so we can coordinate pivotal trials in countries across the world using the safest cell manufacturing protocols, the most predictive biomarkers, and clinical outcome measures that are most meaningful to the global SCI community.