Analysis from Experts| Pro. Nikhil C. Munshi: Application and In-depth Analysis of BCMA-CART in Multiple Myeloma
Editor's note: In recent years, chimeric antigen receptor T cell (CAR-T) therapy is a hotspot in the field of hematological malignancy. For multiple myeloma (MM), especially relapsed and refractory MM (RRMM), BCMA-CART shows extremely high remission rate and brings new treatment options for RRMM patients. In 2020 ASCO meeting, abstract 8503(KarMMa study) shows that BCMA-CART can treat RRMM patients effectively, and toxicity is also manageable. To better understand the application of BCMA-CART in field of MM, we invited Professor Nikhil C. Munshi (the first author of KarMMa study) to make a comprehensive analysis of BCMA-CART and some other related topics
Q1: What is the functioning mechanism of BCMA-CART therapy? Why is it so efficient?
Prof. Munshi: CAR-T cells are modified normal immune cells from the patient in the autologous setting that are modified so that the tumor cells are recognized by the immune cells. Now in myeloma, the BCMA is the target currently, and BCMA is expressed only on myeloma cells and normal plasma cells, but no other cells in the body. So,when the CAR-T is associated and infused with this specificity, it only goes to the tumor cells in the bone marrow and or wherever the tumor cells are. So,the first thing that it makes it specific. The second is that the killing is by immune mechanism how a normal immune cell kills the tumor cells and kills a cell that is infected with virus or others. And so in this case, the killing mechanism is very different than traditional killing by chemotherapy agent, bortezomib and other matters. So, none of the usual resistance mechanism are usually operating, and that's why when we have a specific targeting to BCMA and killing by immune cells, the overall efficacy becomes tremendously high, and that's why when we look at the BCMA directed CAR-T cell therapy by all different companies and different products, the response rates are 80 to 100 percent in very late patient population,and that's the reason the method of killing is able to overcome the traditional resistance mechanism and being able to target specific cells.
Q2：Could you share experience in the diagnosis and treatment of neurotoxicity? And why the incidence of neurotoxicity in KarMMa clinical trials is higher than that of CARTITUTE-1 and EVOLVE?
Prof. Munshi: Neurotoxicity is a serious side effect of CAR-T cell therapy in lymphoma,leukemia and same in myeloma. Neurotoxicity basically means that there is some disturbance of neurological function connected with the CAR-T infusion, we are not going to discuss what causes that, there are multiple reasons, could be T cells it themselves, could be immune reasons, could be inflammatory changes, could be sight of kinds. However, it is graded in a very defined way,it is graded by what is called ICE score, or it is graded by algorithm. Grade one is where patient has some depression of consciousness, but patient can be awakened spontaneously, there are no other immune and neurological side effect. Grade two is when patient is a level of consciousness is low, but he can be only awakened by the wise. Grade three is when patient requires a tactile stimulation for awakening and may or may not have other clinical seizure which are focal or rapid resolving generalized seizure, like with EEG changes, but no other weakness or neurological deficit. Grade four is when we can not awake the patient and are more serious seizures and others.
The management is reasonably straightforward, grade one and two neurological toxicity is typically managed by supportive care, doing the diagnostic workup, giving medicines to prevent seizure, and also to have some way to rule out cerebral edema. Grade three and sometimes even grade two neurotoxicity will then need to be treated more aggressively, patients besides getting the supportive care, they would need to get dexamethasone, usually 10 to 20 mg dose give IVS every six hours or something similar dosages. I'm definitely control procedure using steroid or similar other, and by seizure medication, in some cases, even using higher dose steroid. Tocilizumab is always considered as part of the treatment for it, although it is mainly reserve for treatment of traditionally CRS and grade four toxicity requires all of this about with some other supportive care, which many require hyperventilation, therapy to decrease cerebral edema, et cetera. And also consultation with neuro ICU colleagues to have more active measures, but are very active, quick treatment of neurotoxicity, especially grade three or higher is required.
Now in KarMMa study of 128 patient, the neurotoxicity observed was around 17.3%, however, grade three neurotoxicity was very small,very few patients had grade three neurotoxicity. In the other studies, the EVOLVE study, it was 13.3%, in CARTITUTE-1 is 10.3%. So CARTITUTE-1 and EVOLVE had smaller number of patients enrolled, it will also had a smaller number of patients enrolled 62 and 29, or 29 and 62. So, basically between 10 to 17% is the range i wouldn't call one having a higher neurotoxicity or other having a lower neurotoxicity, i think the neurotoxicity range remain is from 10 to 20%. In this patient population, in almost all of this study, it has been predominantly grade one and two neurotoxic city, so grade three is quite infrequent. So, in general, i would feel that in myeloma compared to other malignancies, the neurotoxicity frequency is smaller, meaning less frequent, and also is of lesser intensity. In KarMMa study, for example, grade three was 3%, i don't think neurotoxicity is a major concern in BCMA directed CAR-T cell therapy.
Q3： What is the relationship between the dose of BCMA-CAR T cells and the adverse effect? How to determine the optimal dose for infusion? Is it possible or necessary to define a personalized infusion dose?
Prof . Munshi: That's a very important question, the dose of CAR-T cells and response,dose of CAR-T cells and toxicity. So, in the KarMMa study, there was clear dose response relationships identified. patients getting 150×106 , 300×106 cells and 450 ×106 cells, 450×106 being over target dose. There was a clear increase in people having overall response and the complete response,so i think maintaining a higher dose is important. But similarly, there is also some relationships with dose and the CRS, 150×106 cells, the CRS was 50%, 300×106 cells, it was 76%,450 ×106 cells, it was 96%. But importantly, the CRS in every all of these does range was of the lower intensity. So CRS and dose is not a major concern, 450 ×106 cells which is the higher dose is not a dose with significantly high grade CRS, so i think maintaining the higher dose for 450×106 cells in KarMMa study is important, because the responses are higher. And very clearly, duration of response is also significantly higher if you look at the patients having 450 ×106 cells, the PFS was 12 months,and i think that's a very important number to keep in mind, so i think maintaining the higher dose is important.
For neurotoxicity, no clear dose response relationship was observed, so higher dose doesn't mean higher neurotoxicity,and same beside opinion is not connected. So, i think currently we need to use the higher dose where we get better efficacy, and also higher frequency of CRS but not the higher grade of CRS, so i think currently the plan would be to go for the higher dosage and there is less requirement to individualize the dose. Now, when other products will become available from other companies and other investigators, then we will have to study if there is any need for personalized dose where we can give the CAR-T cell based on the body weight or blood volume, or some such measures. But currently, a fixed dose in KarMMa study was good enough to give both high response rate and manageable CRS.
Q4： What do you think the reason for the relapse after CAR-T therapy? Is there indicator that can predict CAR-T relapse?
Prof. Munshi：That is also a very important question, we and others are really studying what is the reason for relapse after CAR-T cells. From the current smaller studies done all over, including the KarMMa study and the other study, it looks like loss of BCMA is not the primary reason,there have been few cases that have been observed,but that's not the primary reason, only a small number of cases. So, one of the important point would be lack of persistence, the CAR-T cells don't stay survive very long and that may be one of the reason for relapse. Number two, the change in the immune microenvironment could be major issue. Number three, that we still need to study is that some of the sites,extramedullary sites where tumor may be able to have a shelter and be protected from CAR-T cells,and that could be, in some of the cases, part of the reason and also the immune and non immune microenvironment in the bone marrow as well as in the body, can be playing some role.
So, i think the relapse after CAR-T cells are probably connected with multiple different mechanisms, lots of BCMA being a minor, real but minor reason in this case, so, once we study about what drives this will be able to tell us how to overcome it. And more important point right now is the CAR-T cells are given as one infusion, no maintenance, in myeloma, no treatment is like that, for even after transplant, we have a long lenalidomide maintenance. So, I think to prevent relapse will have to come up with strategies that will maintain very good and deep responses when we get CAR-T therapy.
Q5：How is the efficacy of bridging therapy in KarMMa trial? Is it possible to use CAR-T therapy in other therapeutic stages in the future?
Prof. Munshi: I think that's a very important and a very good question, your observation is very true, 88% patients in the KarMMa study require bridging therapy that tells you that patients are very aggressive myeloma, and that we can not even hold it without treatment for four to five weeks. But, it's a good initial result that establishes the proof of principle that CAR-T cells work very well, very deeply and can provide reasonably long term remission. Now, the task is what you're asking can now will be doing it sooner, and the answer is absolutely true, for multiple reason, it would be good to use CAR-T now in second line and maybe newly diagnosed cases,because that's where the sensors are very sensitive,there are still not extramedullary,so there may not have sanctuary sites and can be very effectively killed,so that's one very good reason. Number two is what you said, the tumor burden does affect the CRS, high tumor burden, more CRS, more toxicity, so we may now need to learn to first bring down the tumor burden and then CAR-T could be more effective. So, there are a number of studies ongoing currently at an earlier stage of the disease in second line treatment, there are CAR-T cells are ongoing in newly diagnosed patients with high risk myeloma so that they can be treated, also in patients who are coming out of transplant with residual disease, or relapsing quickly after transplant is another setting where we are studying CAR-T cells.
So, i think in very near future, you will see a number of studies where CAR-T cells are being utilized at an earlier stage of the disease, and this is where its main action and main utilization will happen in future so that we might be able to even cure this. This is very soon.