The inMMyCAR study is a study of using in vivo CAR-T in patients with multiple myeloma. In vivo CAR-T is essentially a lentiviral vector which has a modified envelope such that it is able to target specifically T-cells using a CD3 single-chain variable fragment, together with a modification of a particular protein in the vector called VSV-G, which is vesicular stomatitis virus glycoprotein. What that does is that normally in lentiviral gene therapy the entry of the vector into cells is through the LDL receptor or low-density lipoprotein receptor, and by mutating that it inhibits the binding but maintains what we call the fusogenic activity. So it maintains transduction efficiency but because it’s targeted against CD3 the vector is able to specifically target the patient’s T-cells. Doing that it brings a transgene which encodes the chimeric antigen receptor which is directed against myeloma antigen B-cell maturation antigen and the overall effect is therefore to convert a patient’s own T-cells into CAR T-cells and that’s why it’s called in vivo CAR-T.
So this first in human trial provides the opportunity to use this mechanism of doing in vivo CAR rather than what is the current technology, already approved technology, of using CAR T-cells that are manufactured ex vivo, that is in a laboratory.
What was the study design?
The design is a phase I classical 3x3 design such that we start at dose level 1 and with the 3x3 design then proceed to different dose levels according to toxicity and safety and tolerability.
What were the key results?
The key result is that in four patients treated so far all of them have achieved minimal residual disease negativity at month 1. Moreover, two out of the four patients are still MRD negative at month 3. In addition, this is associated with increasing depth of response which we use the International Myeloma Working Group. The first patient has achieved a complete response, the others are still in partial response which we believe is due to the clearance half-life of the paraprotein whereby it takes longer for the paraprotein to clear. Hence we are expecting, given the MRD negativity, for the responses to progressively deepen and this is consistent with also soluble BCMA which we measure as a correlative assessment of tumour load.
The other aspect of the trial results is the safety and we found the safety profile to be very favourable. In particular, the cytokine release syndrome, which is a known effect of CAR T-cells, all cases were just grades 1-2 while there was no neurotoxicity, either immune effector cell associated neurotoxicity, namely ICANS, or delayed neurotoxicity. One particular important result is that there was minimal cytopenia. So the only grade 4 cytopenia was one case of neutropenia which occurred almost immediately after the infusion, shortly after infusion, and it only lasted 16 hours, within the 16 hours, because that’s when we did the next blood count. We think that’s due to neutrophil margination it then normalised. Otherwise all the cytopenias were of very short duration and we also therefore feel that, due to the favourability of this profile, that it is possible, especially with the low level cytopenia, that this treatment could even be given as an outpatient in the future if the results continue to reflect the first four patients.
What is the clinical significance of these results?
Obviously it’s very early days in the sense that it’s a first in human and we only have four patients but the reason why it was able to be presented as a late breaker is because it is a very innovative methodology and it produced 100% MRD negativity with minimal toxicity. So, on that basis, I do believe that this treatment has the potential to be transformative in the landscape of CAR-T therapy in myeloma.
What are the next steps for advancing KLN-1010 in clinical development?
Obviously we are continuing to perform this particular trial and, in fact, since the talk I gave at ASH we had one patient dosed just the day before and another patient that I actually just dosed yesterday. So obviously we are continuing this trial.
I’d like to add that these patients are being dosed at one level, so dose level -1, and that’s not because of the toxicity but it was in view of the fact that the efficacy was so high, whether we could even further reduce any toxicity or improve the safety profile by exploring the therapeutic windows. Maybe we can achieve similar efficacy with even one dose level lower. Hence we are exploring this dose level -1 and according to this cohort of three patients, being a 3x3 design, we will then decide what the next dose cohort will be as well as expanding the trial. The overall plan is to treat 20 patients in the dose escalation phase and then following this will be to treat another approximately 20 patients in a dose expansion.
I will mention, not that it is of significant concern at present, is that there were infusion-related reactions which were very easily controlled, in fact. There was one reaction at dose level -1 that I presented at the time and this only required paracetamol whereas the other two reactions were able to be controlled by dexamethasone tocilizumab. So I’m trying to explain that it’s well worthwhile to see if we can even make the profile even better to enable outpatient treatment hopefully for the future.
