Cytokine release syndrome

Across all of those animals, we're of course monitoring the generation of cytokines.

CRS is something that's pretty well understood within the CAR T field, which stands for cytokine release syndrome, and it's something that had to be managed extensively for patients who receive CAR T therapy to the point where the, um, the sites that are allowed to administer CAR T therapy have to be certified to do so, specifically because they are qualified to manage the CRS symptoms.

So it's a, it's a big issue.

We're creating a, a massive cytokine storm inside these patients, especially when the CAR T-cells start to grow and grow.

But what we didn't see was a huge cytokine reaction to the virus infusion, and I think that's kind of important.

We, we expected to see an infusion reaction in these animals, and we saw much less of it than what we were anticipating.

And I think that's hopefully a positive sign for, you know, these first patients who are going to be dosed with our vector, because the infusion reaction is something that you, you, you don't know exactly how it's going to proceed until you've started to dose patients, and you want to make sure that it doesn't pose this additional on top of the CRS kind of a risk for, for patients who are receiving this type of therapy.

So, you know, we're not the first to do, to dose a patient with an in vivo CAR T, and we've seen a pretty wide spectrum of what this infusion reaction looks like depending on who generates the vector.

So the registry, the BNT registry, helped a lot with some joint effort with the other hematological societies such as EHA and also partner society in deepening understanding how the different toxicities could be handled and early recognized.

So after the early events like the severe CRS, cytokine release syndrome, and immune effector cell-related neurological toxicity, The ICANNs and CRS are nowadays more manageable, especially because we feel more confident in establishing an early treatment for preventing the massive effect of the cytokine storm, which is related to the CAR T.

We also know how the disease burden is clearly impacting on the cell therapy effect.

And with the possibility of advancing the line of treatment earlier in the disease phase of the patient, this is helping a lot in managing this kind of toxicity.

Early acute toxicity such as CRS and ICANN attracted a lot of attention from the start.

And are they still a main concern?

CRS and ICANN are the main early events related to the toxicity of CAR-T. and are mainly due to the effect of the reaction, the cell reaction of the patients after the infusion of the product.

Nowadays, we know that also with more sophisticated products, the toxicity and the difference in the construct of the CAR-T itself, the toxicity is earlier and with less lower grade of toxicity.

So the toxicity profiles are very different from bispecifics in many ways.

where the CRS and ICANNs, although encountered, the rates are much lower, the severity is lower as well.

And as we have seen, Raj, with some of these recent studies, including this Monviso study, which was presented by my colleague, Dr. Saurabh Chhabra from Mayo, Arizona, where the use of prophylactic tocilizumab, in fact, led to 0% CRS.

Granted that these numbers were small, but these data were very, very impressive.

Now, etentamic, which was the drug that trial utilized, it's another anti-BCMA bispecific that was utilized.

It's given after the first step-up dose, it's given only once every four weeks and also has reduced... interaction or affinity rather with CD3, thereby making it more appealing for use because of reduced incidence of CRS.

So overall, even without the use of prophylactic TOSI, CRS rates were low to begin with the tentamic,

but 0%

But I think it is an important treatment for us.

Incidentally, when you say difficult treatment, does that kind of come down to more CRS?

Yes, the logistics of doing it and the CRS and the monitoring that needs to be done and the expertise you need to have to manage the toxicities that we see with that treatment.

All right, well, let's take a look at this survey, and to me, this is my favorite part of this Grand Rounds series.

I watched a lot of these virtually, and whenever we get into these scenarios, the audience gets very engaged.

But now, only one year before they have progressive disease.

Now, everybody says pertabrutinib, but you say pertabrutinib bridged to CAR-T.

So, first of all, can you talk about, in that situation, what you would consider eligibility? You mentioned the fact there's more CRS.

about two weeks ago.

So far, she's tolerated the treatment, hasn't had any adverse events, including no ICANS, no CRS of significance, but I'm monitoring very closely to understand how the use of Tarlatimab, if it could impact the course of her LEMS.

So interesting.

I probably shared with you because I've shared with a lot of people inside and outside of lung cancer.

and lymphoma for a long time but when we heard about it in small cell we were like oh my god these people are in the hospital they're sick they're gonna have full blown they got a lot of disease they're gonna have a lot of crs any idea about why we haven't seen more crs

I don't exactly know why, except for, you know, maybe it's lessons learned with the other studies that have been done, for example, in hematologic malignancies, you know, the use of the pre-medications and use of steroids.

I think it's very effective in mitigating the risk of CRS.

And also, I think the step-up dosing that we are employing to mitigate the risk of CRS.

Although the overall incidences have been higher in Cilta-cel, it's really kind of driven by the dual BCMA binding effects of the structure of Cilta-cel in comparison to Ida-cel, which only has one BCMA-targeted antigen.

So overall, when we look at kind of the overall incidences and any particular risk factors that are associated with this, similar to some of our other toxicities like CRS and ICANS, having a higher baseline IL-6 level and increased tumor burden have consistently kind of shown patients are at higher risk for developing this particular toxicity.

Additionally, and I think something that will kind of encompass all of these atypical toxicities is kind of an increased recognition of higher peak ALC within the first three weeks post CAR T, kind of driving some of these inflammatory responses.

I think one of the key aspects in terms of management is that, you know, unlike some other disorders, cranial neuropalsies are very responsive to corticosteroids, as well as the introduction of IVIG supplementation as well.

You might also see it referred to as an IEC-associated Parkinsonism.

It tends to occur in about 5% of patients that are receiving the BCMA-targeted CAR T-cell therapies, again, mostly with those patients that are treated with cell-to-cell for the reasons that Becca went over earlier with the cranial nerve palsies.

Although some of the symptoms of this could overlap with ICANS, really these MNT symptoms typically exhibit a delayed onset well after the resolution of CRS and ICANS.

So the median onset of these symptoms is around one month in reported cases, but it has a pretty broad range.