Unlocking Prostate Cancer Treatment: The Pathway of CAR T Targeting Prostate Stem Cell Antigen - Tanya Dorff
June 21, 2023
Tanya Dorff shares her team’s insights on research into CAR T therapy targeting Prostate Stem Cell Antigen (PSCA). Their analysis shows promise in managing advanced castration-resistant prostate cancer. However, this treatment also presents challenges, including the issue of dose escalation due to the occurrence of high-grade cystitis, a complication encountered during the trials. In response, Dorff's team intends to open a phase one B trial to explore the potential of multiple dosing and combination strategies. The team has also observed some promising correlations from using MRI to monitor target bone lesions. Furthermore, their research is focusing on enhancing CAR T-cell efficacy and analyzing diverse patient samples to better understand treatment responses. Dorff emphasizes their commitment to maximizing efficiency in their future trials and shares a hopeful outlook for the potential of CAR T-cell therapy in providing durable remissions.
Biographies:
Tanya Dorff, MD, Associate Professor, Department of Medical Oncology & Therapeutics Research, Section Chief of the Genitourinary Disease Program, City of Hope, Duarte, CA
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Tanya Dorff, MD, Associate Professor, Department of Medical Oncology & Therapeutics Research, Section Chief of the Genitourinary Disease Program, City of Hope, Duarte, CA
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here with Dr. Tanya Dorff, who's a professor of medicine at City of Hope. Thank you so much for being here with me today.
Tanya Dorff: Thanks for having me.
Alicia Morgans: Wonderful. So Tanya, you and your team put together a really interesting analysis on CAR T targeting PSCA, and this was discussed at a poster discussion session at ASCO 2023. Can you tell me a little bit about it and really kind of help us understand this PSCA target?
Tanya Dorff: Yeah, so prostate stem cell antigen has some similarities to what people are more familiar with, PSMA, so it's an androgen regulated gene. It's more commonly expressed in advanced castration-resistant prostate cancer. So it's very commonly expressed similarly to PSMA, making it a good target for therapy. One of the things we like about it as a target is that there's little expression on normal tissues. There is some in the bladder, and we did encounter problems on that basis during the dose escalation. But you don't get some of the other on-target, off tumor toxicities that you might see with PSMA targeted pharmaceuticals.
Alicia Morgans: Okay. So you've designed CAR Ts against this PSMA and you and the team have been using them for several years at this point. Tell me a little bit about the work that was presented at ASCO this year.
Tanya Dorff: We presented an update. So we had shown a little bit of the early data a year ago at GU ASCO showing that we did have some therapeutic efficacy, but we had encountered the dose limiting toxicity of cystitis. So rather than escalating the dose further up to 300 million, which we do think will be a more effective dose, but in the mouse models, when we went back to the lab, we saw that that would almost certainly provoke high grade cystitis. We've decided to close the phase one, even though technically it's safe and we could expand or escalate. And instead we're opening a phase one B where we'd like to study multiple dosing as a strategy and some combinations that we hope will augment the efficacy. So we're presenting essentially the final data set for the phase one trial. We added a third cohort, which was the same dose of CAR T-cells, a hundred million, but we lowered the dose of the cyclophosphamide, which is part of the preconditioning regimen or what's sometimes called lympho depletion.
And with that we did find absence of the high grade cystitis, so it was definitely the CAR T-cells, but also a contribution from the chemo. Because having worked with other CAR T cells such as PSMA targeting CAR T-cells, you don't see cystitis even though you use the cyclophosphamide. So we managed to work that out, but we are not seeing quite as much efficacy. Our CAR T-cells persisting as long as we'd like. So we think with the multi-dose strategy with some other manipulations and combination strategies, we're hoping to see greater efficacy in the phase one B.
Alicia Morgans: Okay. And what efficacy measures did you look into and what kind of trends did you see?
Tanya Dorff: So we did measure PSA, and interestingly we did have some discordance where patients would have reduction in cancer related pain and improvement on scans, but their PSA would not go down. So unclear if that's the best marker. And we were looking really early. So our efficacy assessment was at day 28.
Alicia Morgans: Oh wow.
Tanya Dorff: We also did conventional imaging, CT and bone scans. An interesting correlate that was embedded in the trial was MRI of a target bone lesion. So we're all vexed by looking at a bone scan. And you can know a patient's doing well in the bone scan can look the same or it can look worse or it might look better. But MRI as it turns out, can actually show reduction in a tumor in a bone and reduction in enhancement. So with the exceptional responder that we had, not only did a soft tissue metastasis disappear, but also the target bone metastases that we had selected for MRI imaging clearly showed improvement on the MRI.
Alicia Morgans: Wow.
Tanya Dorff: So imaging of course, is a problem in prostate cancer advanced treatments. People have been asking why we didn't use PSMA PET and PSCA and PSMA may have similar expression, but we're not sure whether that would be the better way to image these patients.
Alicia Morgans: Well, there are so many questions that I'm glad that you and the team were able to sort of put a stake in the ground and say this is what we're going to do. The MRI information is really, really intriguing and so I look forward to hearing more about that over time as well.
Tanya Dorff: We also have circulating tumor cell data from Peter Kuhn, so that's been really interesting. He does this very broad platform that finds cells of interest that aren't necessarily only classical CTCs. But what we presented here was the cytokeratin positive or more classical CTCs, and we definitely saw decreases in CTCs after the CAR T treatment. And because of our time points, we're actually able to see that it's more related to the CAR T and not just to the lympho depletion chemo. We see differences between the kinds of CTCs in the marrow and the peripheral blood. So we are trying to learn as much as we can from every patient we've treated. And we're grateful to be partnering on that front with UPenn and other institutions through the PCF Tactical Award because we want to get this right. We think CAR T-cells can get to a level of durable remissions, and we just need the science to guide us as to how to do that. So to maximize efficiency as we plan our future trials, having these collaborations will be really valuable.
Alicia Morgans: Absolutely. And tell me a little bit about the tactical award, because I think that the goal of this particular award type, and there were only a few, maybe three given out, for teams that were multi-center, were really innovative, big risk, big reward type projects. Congratulations on getting that award. It was no small feat. And tell me a little bit about what you and the team are doing for that award.
Tanya Dorff: So I'm one small, very small part of this giant award, and we are so grateful to PCF. We think it shows a real commitment to making this technology work. So a lot of the teams are looking at ways to enhance the CAR T-cell efficacy through different ways we can engineer them. The part I'm involved in will include analyzing our samples. We're hoping not only from our own trial and Upenn's own trial, but also maybe some of the industry partners if we can get samples from them. Because the more power we have, the more numbers, then we can start to understand why these exceptional responders and these didn't. Was it something in the tumor microenvironment? So we're doing digital spatial pathology on the biopsy samples. And then moving forward as we have new patients being accrued to CAR T trials, we will kind of standardize the kinds of correlative science we're doing across institutions again to try to just amplify the power to learn what we need to learn.
We're also really excited to be doing rapid postmortem tissue collection as part of the tactical award. So City of Hope has a legacy project. It's traditionally been for breast cancer. But prostate cancer, one of the reasons we lack as much understanding as we need is because we can't get at what's different in the different metastases. We know there's heterogeneity, but it's hard to put patients through multiple biopsies. So we're hoping that we'll be able to study normal tissues like the bladder, multiple sites of disease, and understand why some sites of disease might respond better to others through this unique opportunity from the grant.
Alicia Morgans: Wonderful. Well, as we start to wrap up, I'd love to hear, other than the cystitis, what kind of side effects and things should we be thinking about as you and the team and your tactical team as well, are moving forward with the CAR T approach?
Tanya Dorff: CAR T-cell toxicity is formidable. Cytokine release syndrome is one of the things we think about very commonly. With prostate cancer, CAR T-cell therapy, we haven't seen quite as much cytokine release or quite the high degree that maybe you see with the bispecifics. But you do get some cytokine release and it does probably portend response, indicates T-cell activation. So that can be managed with tocilizumab. With ours, we did not see any of the neurologic toxicity, thankfully, what they call ICANs, but that has been seen with some of the other CAR T cells. Also macrophage activation when you get excessive expansion and then you set off other cytokines that drive really negative parts of the immune system. So thankfully, again, we did not see that with our CAR T-cell, but it is something that's been seen. So it's really important to work all of this out and get some better defined algorithms for how to manage these unique and serious complications before this could become a treatment that could be rolled out more broadly.
Alicia Morgans: Absolutely. Well, I'd love to hear a final word in summary on this really exciting presentation.
Tanya Dorff: In summary, I think CAR T-cell therapy is challenging to bring into solid tumors generally. We're doing work with regional instillation like intraperitoneal for ovarian cancer at City of Hope. So we have to come up with innovative strategies to translate the dramatic success that these agents have had in hematologic malignancies into solid tumors. And prostate cancer presents its own set of very unique challenges, but we will get there. We see that we can get dramatic responses. And now we just have to go back and do the science and do the work. Patients are really asking for this. It gives them a tremendous amount of hope to know that someone's looking at a treatment that has the potential for a long-lasting remission rather than temporary response and then resistance. So we're not there yet, but we'll get there.
Alicia Morgans: Wonderful. Well, I commend you and the team. And I appreciate the patients who participate in this work. And I also want to say that I think it's phenomenal that you and the team and your tactical team are also looking at every bit of information you can glean. Whether a trial is the slam dunk that you think in terms of efficacy, or whether it's a step along the path to really creating these therapies, you're learning everything you possibly can. And it absolutely gives hope not only to the patients but to the field as we continue down this path. And I congratulate you and thank you for your time.
Tanya Dorff: Thanks so much.
Alicia Morgans: Hi, I'm so excited to be here with Dr. Tanya Dorff, who's a professor of medicine at City of Hope. Thank you so much for being here with me today.
Tanya Dorff: Thanks for having me.
Alicia Morgans: Wonderful. So Tanya, you and your team put together a really interesting analysis on CAR T targeting PSCA, and this was discussed at a poster discussion session at ASCO 2023. Can you tell me a little bit about it and really kind of help us understand this PSCA target?
Tanya Dorff: Yeah, so prostate stem cell antigen has some similarities to what people are more familiar with, PSMA, so it's an androgen regulated gene. It's more commonly expressed in advanced castration-resistant prostate cancer. So it's very commonly expressed similarly to PSMA, making it a good target for therapy. One of the things we like about it as a target is that there's little expression on normal tissues. There is some in the bladder, and we did encounter problems on that basis during the dose escalation. But you don't get some of the other on-target, off tumor toxicities that you might see with PSMA targeted pharmaceuticals.
Alicia Morgans: Okay. So you've designed CAR Ts against this PSMA and you and the team have been using them for several years at this point. Tell me a little bit about the work that was presented at ASCO this year.
Tanya Dorff: We presented an update. So we had shown a little bit of the early data a year ago at GU ASCO showing that we did have some therapeutic efficacy, but we had encountered the dose limiting toxicity of cystitis. So rather than escalating the dose further up to 300 million, which we do think will be a more effective dose, but in the mouse models, when we went back to the lab, we saw that that would almost certainly provoke high grade cystitis. We've decided to close the phase one, even though technically it's safe and we could expand or escalate. And instead we're opening a phase one B where we'd like to study multiple dosing as a strategy and some combinations that we hope will augment the efficacy. So we're presenting essentially the final data set for the phase one trial. We added a third cohort, which was the same dose of CAR T-cells, a hundred million, but we lowered the dose of the cyclophosphamide, which is part of the preconditioning regimen or what's sometimes called lympho depletion.
And with that we did find absence of the high grade cystitis, so it was definitely the CAR T-cells, but also a contribution from the chemo. Because having worked with other CAR T cells such as PSMA targeting CAR T-cells, you don't see cystitis even though you use the cyclophosphamide. So we managed to work that out, but we are not seeing quite as much efficacy. Our CAR T-cells persisting as long as we'd like. So we think with the multi-dose strategy with some other manipulations and combination strategies, we're hoping to see greater efficacy in the phase one B.
Alicia Morgans: Okay. And what efficacy measures did you look into and what kind of trends did you see?
Tanya Dorff: So we did measure PSA, and interestingly we did have some discordance where patients would have reduction in cancer related pain and improvement on scans, but their PSA would not go down. So unclear if that's the best marker. And we were looking really early. So our efficacy assessment was at day 28.
Alicia Morgans: Oh wow.
Tanya Dorff: We also did conventional imaging, CT and bone scans. An interesting correlate that was embedded in the trial was MRI of a target bone lesion. So we're all vexed by looking at a bone scan. And you can know a patient's doing well in the bone scan can look the same or it can look worse or it might look better. But MRI as it turns out, can actually show reduction in a tumor in a bone and reduction in enhancement. So with the exceptional responder that we had, not only did a soft tissue metastasis disappear, but also the target bone metastases that we had selected for MRI imaging clearly showed improvement on the MRI.
Alicia Morgans: Wow.
Tanya Dorff: So imaging of course, is a problem in prostate cancer advanced treatments. People have been asking why we didn't use PSMA PET and PSCA and PSMA may have similar expression, but we're not sure whether that would be the better way to image these patients.
Alicia Morgans: Well, there are so many questions that I'm glad that you and the team were able to sort of put a stake in the ground and say this is what we're going to do. The MRI information is really, really intriguing and so I look forward to hearing more about that over time as well.
Tanya Dorff: We also have circulating tumor cell data from Peter Kuhn, so that's been really interesting. He does this very broad platform that finds cells of interest that aren't necessarily only classical CTCs. But what we presented here was the cytokeratin positive or more classical CTCs, and we definitely saw decreases in CTCs after the CAR T treatment. And because of our time points, we're actually able to see that it's more related to the CAR T and not just to the lympho depletion chemo. We see differences between the kinds of CTCs in the marrow and the peripheral blood. So we are trying to learn as much as we can from every patient we've treated. And we're grateful to be partnering on that front with UPenn and other institutions through the PCF Tactical Award because we want to get this right. We think CAR T-cells can get to a level of durable remissions, and we just need the science to guide us as to how to do that. So to maximize efficiency as we plan our future trials, having these collaborations will be really valuable.
Alicia Morgans: Absolutely. And tell me a little bit about the tactical award, because I think that the goal of this particular award type, and there were only a few, maybe three given out, for teams that were multi-center, were really innovative, big risk, big reward type projects. Congratulations on getting that award. It was no small feat. And tell me a little bit about what you and the team are doing for that award.
Tanya Dorff: So I'm one small, very small part of this giant award, and we are so grateful to PCF. We think it shows a real commitment to making this technology work. So a lot of the teams are looking at ways to enhance the CAR T-cell efficacy through different ways we can engineer them. The part I'm involved in will include analyzing our samples. We're hoping not only from our own trial and Upenn's own trial, but also maybe some of the industry partners if we can get samples from them. Because the more power we have, the more numbers, then we can start to understand why these exceptional responders and these didn't. Was it something in the tumor microenvironment? So we're doing digital spatial pathology on the biopsy samples. And then moving forward as we have new patients being accrued to CAR T trials, we will kind of standardize the kinds of correlative science we're doing across institutions again to try to just amplify the power to learn what we need to learn.
We're also really excited to be doing rapid postmortem tissue collection as part of the tactical award. So City of Hope has a legacy project. It's traditionally been for breast cancer. But prostate cancer, one of the reasons we lack as much understanding as we need is because we can't get at what's different in the different metastases. We know there's heterogeneity, but it's hard to put patients through multiple biopsies. So we're hoping that we'll be able to study normal tissues like the bladder, multiple sites of disease, and understand why some sites of disease might respond better to others through this unique opportunity from the grant.
Alicia Morgans: Wonderful. Well, as we start to wrap up, I'd love to hear, other than the cystitis, what kind of side effects and things should we be thinking about as you and the team and your tactical team as well, are moving forward with the CAR T approach?
Tanya Dorff: CAR T-cell toxicity is formidable. Cytokine release syndrome is one of the things we think about very commonly. With prostate cancer, CAR T-cell therapy, we haven't seen quite as much cytokine release or quite the high degree that maybe you see with the bispecifics. But you do get some cytokine release and it does probably portend response, indicates T-cell activation. So that can be managed with tocilizumab. With ours, we did not see any of the neurologic toxicity, thankfully, what they call ICANs, but that has been seen with some of the other CAR T cells. Also macrophage activation when you get excessive expansion and then you set off other cytokines that drive really negative parts of the immune system. So thankfully, again, we did not see that with our CAR T-cell, but it is something that's been seen. So it's really important to work all of this out and get some better defined algorithms for how to manage these unique and serious complications before this could become a treatment that could be rolled out more broadly.
Alicia Morgans: Absolutely. Well, I'd love to hear a final word in summary on this really exciting presentation.
Tanya Dorff: In summary, I think CAR T-cell therapy is challenging to bring into solid tumors generally. We're doing work with regional instillation like intraperitoneal for ovarian cancer at City of Hope. So we have to come up with innovative strategies to translate the dramatic success that these agents have had in hematologic malignancies into solid tumors. And prostate cancer presents its own set of very unique challenges, but we will get there. We see that we can get dramatic responses. And now we just have to go back and do the science and do the work. Patients are really asking for this. It gives them a tremendous amount of hope to know that someone's looking at a treatment that has the potential for a long-lasting remission rather than temporary response and then resistance. So we're not there yet, but we'll get there.
Alicia Morgans: Wonderful. Well, I commend you and the team. And I appreciate the patients who participate in this work. And I also want to say that I think it's phenomenal that you and the team and your tactical team are also looking at every bit of information you can glean. Whether a trial is the slam dunk that you think in terms of efficacy, or whether it's a step along the path to really creating these therapies, you're learning everything you possibly can. And it absolutely gives hope not only to the patients but to the field as we continue down this path. And I congratulate you and thank you for your time.
Tanya Dorff: Thanks so much.