Christina Lingham: | Hi everyone. I'm Christina Lingham from the PEGS Europe Summit. I am thrilled to have the opportunity to speak with Hinrich Abken, to talk about how displaying signaling of CAR molecules can be used to redirect the specificity of human t-cells. He will be giving a talk at the display antibodies track, October 31st through November 1st in Lisbon. Hinrich, thank you for joining us. |
Hinrich Abken: | Thank you. |
Christina Lingham: | Dr. Abken, can you explain what first and second generations CARs are and what you think will be next? |
Hinrich Abken: | First of all a CAR is a chimeric antigen receptor is the name for it, and this is chimeric because in the extracellular part it binds to a target, and in the intracellular it drives T-cell activation. Driving T-cell activation, there is a signaling domain derived from the T-cell receptor. Having a CD3-zeta domain, derived from T-cell receptor in a CAR means this is a first generation CAR. Having added a co-stimulation domain to the CD3-zeta means this is a second generation CAR and the background is that you need co-stimulation in addition to zeta signaling in order to drive full T-cell activation. Then researchers sought to combine different co-stimuli in one CAR and this combined co-stimuli, together with CD3-zeta, is a third generation CAR. It comes from one zeta only, zeta plus C28, for example, is the second generation, third generation is zeta plus C28 plus 41BB plus anything else. These are the three generation. When you're asking what will be the next, people are saying the next generation is the post generation. The post generation we invented some years ago, two years ago now. This is a CAR T-cell of one, two, three generations, doesn't matter and has an additional payload. The additional payload is a transgenic protein that is released upon CAR signaling. We have a CAR T-cell, engages target then releases a second protein that may be inside an enzyme or something like that and then drives the secondary immune response. The name for that was supposed to be the first generation, but we say this is a CAR with a payload and the CAR with a payload is obviously a TRUCK so we call it TRUCKS. |
Christina Lingham: | How would you say CARs compare with T-cell receptors? |
Hinrich Abken: | The CAR is a very primitive T-cell receptor in that way. The T-cell receptor is a complex structure with a number of molecules that need to come together to drive T-cell activation. It's a very sensitive, sensitizing system for targets. A CAR is, in this sense, a very primitive one that uses an antibody, requires two [inaudible 00:03:10] amount of antigens to be recognized, has a signaling change just linked and operates in that very primitive, less sensitive way as the TCR. As the CAR work without recognizing the MHC complex and it recognize only targets on the surface of target cell. It recognizes a broad variety of targets, it's not the case for the TCR. The TCR recognizes targets only in the context of pMHC. There are some advantages and disadvantages when comparing CAR and TCR. |
Christina Lingham: | Can you also talk about the pros and cons of CAR versus like ... |
Hinrich Abken: | As it's name says, a bi-specific T-cell engager, this is a recumbent antibody that recognizes on one side C3 as the component of TCR and on the other side an antigen that is expressed by a cancer cell or any other target. This molecule links together the T-cell to a target cell. A CAR does it in a similar way, it binds the target on the target cell and is anchored in a T-cell and that is the difference. CAR does not need to bind to a T-cell, it's already attached to the T-cell and the T-cell is driven by the CAR towards the target cell. Using BiTEs you need three components at the same place, the target cell, the T-cell, and the BiTE. In case of, CAR T-cells only need two, the CAR T-cell and the target. The advantage of BiTE of course, it is a product[inaudible 00:04:57] antibody drug product that can be applied to the patient by infusion, does not need any further modification and is active. While the CAR T-cell has to be engineered specifically for each individual patient, and then applied to the patient. It's a living drug, a BiTE is, if you want a classical or a dead drug, that binds or links T-cells to a target cell. |
Christina Lingham: | Hinrich, tell us about your approach, if you could describe it briefly, and then what's unique about it. How it differs from other approaches? |
Hinrich Abken: | Our approach is, CAR T-cell is a payload. As I said, these so called TRUCKS, I used as a living factory let's say, to deliver a product to certain places in the body. I'd like to give you an example. Using a CAR T-cell that is directed by the CAR throughout gastrointestinal carcinoma. The CAR T-cell goes to that carcinoma, going to be activated by the CAR, it now produces a cytokine. Let's say IN first, it's usually not produced by T-cells, so the IN first is accumulating in the tumor and IN first is attracting innate immune cells. These cells are activated in order to cure the other cancer cells that may be not visible to the CAR T-cell. This is an approach that is far beyond, let's say CAR T-cell only. This is a CAR redirected living drug producing a transgenic protein that is cell critically active in the near tumor and [inaudible 00:06:44]. That is our approach and that is new. |
Christina Lingham : | It sounds like in that way it improves upon other current efforts with CAR molecules. |
Hinrich Abken: | Absolutely yeah. |
Christina Lingham : | If CARs are displayed on T-cells how do they kill cancer? |
Hinrich Abken: | If procedures, as everybody thinks, is that the CAR T-cell goes in close vicinity to the target cell and we can see it by living microscopic attaching to the target cell and the CAR is accumulating in spots and find that system, super molecular clusters then gives the activation signal to the T-cell. The T-cell will then secrete cytolitic granular, which include for example, perforin, granzymes, A, B and so forth may pour into the target cell and the target cell will go to die by activating [inaudible 00:07:49] signaling pathway, go to the apotheosis. The CAR giving a kiss of death let's say to the target cell. Then it goes to the next target cell again, the same procedure, and goes to the next one, next one, next one. It's working around giving kiss of death and the target cell will die. That is the mechanism of it, it's seen and [inaudible 00:08:14], how it works, and it is assumed to take work in [inaudible 00:08:18] in a very similar way. Plus, mediated killing, it seems not to be so important in this context but may happen thus far, as well as cytokine release, that is important, like INF gamma release is very important for tumor destruction as well. |
Christina Lingham : | This is a very exciting year, and the results have been very promising. Do you have advice for people working in this field from your own experience? |
Hinrich Abken: | I'd say it's not an advice but I would like to highlight some cell interests that need to be addressed. What we know is that the CAR T-cells are very effective in treating leukemia lymphoma. It's fine, that's perfect, that's excellent. But, it is not researched so far how to cure solid cancer. As I said, for example, gastrointestinal carcinoma, adenocarcinoma, breast, lung, prostate, and so forth, we have faith in the situation or in moments of [inaudible 00:09:22] and why I meant, for example, the tumor is somehow shielded. That T-cells do not penetrate into the tumor. All these things have to be addressed and if you like to say what is the advice. I would say please address all these things that are solid cancer in order to make the very powerful T-cell attack as a [inaudible 00:09:47] strategy, again solid cancer. |
Christina Lingham : | Just in conclusion, what are some of the most exciting recent discoveries in CAR therapy and has your work changed as a result? |
Hinrich Abken: | We are working since, more than twenty years in the field of chimeric receptors and CARs. I think the most exciting thing during the last years was the first clinical trial, University of Pennsylvania, at Sloan Kettering, at Baylor, at Seattle and so forth showing that second generation CAR T-cells are at the verge of treat leukemia in the very long term. To amuse complete remission for example, in acute pediatric leukemia, that did not respond to any standard treatment so far. In my point of view that is one of the most important steps during the last years. That influenced, of course, our research and the research of all our colleagues I think. To direct this strategy towards clinical application, to think what is the next step of clinical application of CAR T-cells? |
Christina Lingham : | Hinrich, thank you for your time and insights today. We look forward to hearing your talk this October 31st and November 1st in Lisbon. That was Hinrich Abken of the University of Cologne. He'll be speaking at display of antibodies at PEGS Europe. If you'd like to hear him in person, go to pegsummiteurope.com for registration information and enter the key code "podcast". I'm Christina Lingham, thank you for listening. |