T-Cell Engagers in Prostate Cancer Treatment - Neeraj Agarwal
September 22, 2024
Alicia Morgans interviews Neeraj Agarwal about his presentation on T-cell engaging treatments for prostate cancer. Dr. Agarwal discusses the rationale behind T-cell engagers, their potential to bypass the limitations of prostate cancer's cold tumor microenvironment, and the various tumor-associated antigens being targeted. He reviews several bispecific and trispecific T-cell engagers currently in development, highlighting promising results from early-phase trials, particularly those targeting STEAP1 and DLL3 antigens. Dr. Agarwal also addresses the challenges faced by these therapies, including cytokine release syndrome and the development of anti-drug antibodies. The discussion explores strategies to enhance efficacy and reduce side effects, such as combining T-cell engagers with other agents, moving treatments to earlier lines of therapy, and using biomarker-based patient selection. Both speakers emphasize the potential of T-cell engagers to transform prostate cancer treatment while acknowledging the need for further refinement to improve patient accessibility and safety.
Biographies:
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Biographies:
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here today with Professor Neeraj Agarwal, who is joining me after a wonderful presentation at ESMO 2024, where he really explained to us how we should think about T-cell engaging treatments for prostate cancer. Thank you so much for your time, Neeraj. Please tell us a little bit about this.
Neeraj Agarwal: Thank you. It's a pleasure to be here. So T-cell engagers are emerging as a new class of drugs, which hopefully will bypass the limitations posed by the cold tumor microenvironment of prostate cancer. So let's look at the rationale for using T-cell engagers first.
As we know, MHC-TCR engagement and co-stimulation are required for T-cell stimulation in normal circumstances, as we can see here. However, MHC expression is downregulated in cancer cells. T-cell engagers bypass the steps needed for MHC-TCR-dependent T-cell activation by engaging with both CD3 receptors on T-cells and a tumor-associated antigen on cancer cells—the prostate cancer cells in this context—leading to T-cell-mediated killing of cancer cells.
We know that T-cell engagers have shown a lot of promise in hematologic cancers and were first approved for acute lymphoblastic leukemia. In the context of solid tumors, we just saw tarlatamab, which targets DLL3 antigen expressed on neuroendocrine small cell lung cancer, was approved based on promising objective responses seen in the Phase II DeLLphi-301 trial.
So coming back to prostate cancer, there are multiple tumor-associated antigens, as you can see here, which can be targeted by T-cell engagers.
So these are the four bispecific T-cell engagers which have been studied so far, and we do have preliminary data available. And that includes pasotuxizumab, acapatamab or AMG 160, JNJ-081, and LAVA-1201.
So all these were early-phase trials, dose escalation, dose expansion trials, where PSMA was targeted. And what we have seen so far is that PSA 50% responses have ranged from 7% to 32%. And we have seen some objective responses. And we have seen that most of these patients were heavily pre-treated, progressed on ARPI, taxane, and unfortunately, two of these drugs are not being developed further because of the onset of anti-drug antibodies. In the context of AMG 160, it is not undergoing further development, given the toxicities of cytokine release syndrome and the lack of antitumor responses which are durable. LAVA-1201 is still being tested, and we look forward to the data from the dose expansion phase in the near future.
One of the promising antigens I find is STEAP1, which was tested in an early Phase I or early-phase trial, as reported by Dr. William Kelly and team in Cancer Discovery very recently. And let's look at the rationale for developing T-cell engagers against STEAP1. So STEAP1 is associated with cancer cell proliferation, invasion, and epithelial-mesenchymal transition. And it's quite expressed in prostate cancer cells. As we can see here, 87% of patients express STEAP1 antigen.
So in this early-phase trial, a bispecific T-cell engager targeting STEAP1 was associated with quite promising PSA responses if you look at PSA 50% response in heavily pretreated patients. And just to let me—allow me to go back for a second. You can see here, half of the patients had visceral metastasis. Thirty-seven percent of patients had liver metastasis. In this patient population, to achieve a PSA 50% response in 50% of patients and a PSA 90% response in 30% of patients is quite remarkable. The good news was that although CRS was quite common in 72% of patients, it was quite manageable with dexamethasone, interleukin-6 antibody, which is tocilizumab.
Now go back—let's go to another T-cell engager targeting another antigen on cancer cells. And in this case, it is tarlatamab, which I just discussed. It targets DLL3, which is expressed on small cell lung cancer. But for us, for patients with prostate cancer, it can also target those patients who have neuroendocrine differentiated prostate cancer. And we do have some data in this context presented by Dr. Rahul Aggarwal, where we saw objective responses of 10% in these 40 patients. And there were higher responses in patients who had high DLL3 expression. So it looks like patients who had high DLL3 expression may have better responses to tarlatamab. Further studies are coming up, and we look forward to seeing the data of tarlatamab in neuroendocrine prostate cancer.
And fortunately, side effects were not that common. Even though 75% of patients had cytokine release syndrome, only one patient had grade three or more side effects. Neurotoxicity events, which are associated with T-cell effector cells, were also present in 12%. But again, fortunately, only one patient had grade four side effects.
And there's another class of T-cell engager known as trispecific T-cell engagers. These are associated—why they are trispecific—because they have a third binding domain which can be bound to or which can be used to target a new tumor-associated antigen, or which can be used to target another T-cell receptor, or which can be fused to human serum albumin, which can allow the extension of half-life of these agents, thereby allowing them to stay in plasma for a longer time and circulate longer. So in this context, we have seen two trispecifics, one targeting PSMA and one targeting DLL3.
And this is the summary data from these two trispecific T-cell engagers. HPN424 is no longer being developed in this trial, but HPN328, which is a DLL3 trispecific T-cell engager, is being developed further, and we look forward to seeing the data again in the near future.
And the story is not going to finish here. We are going to see more novel T-cell engagers, which are designed to target antigens beyond STEAP1 and PSMA, such as prostate stem cell antigen, KLK2, or immune checkpoints.
And so far what we have learned is that these are new therapies with novel mechanisms of action. Most have manageable safety profiles. However, antitumor activity has been quite subtle. And there are challenges which have been faced by these T-cell engagers, which include presence or onset of anti-drug antibodies, which can affect—compromise—the exposure to this drug, and cytokine release syndrome, which requires many of these patients to be hospitalized, which can strain the healthcare system, and also can increase the cost and inconvenience to the patients, in addition to being life-threatening if they are grade three or four and if they're not managed properly.
And this can be—we can go around these limitations by multiple ways, which include combining with novel agents, combining with... So both side effects. So we can combine them with novel agents at lesser doses, so that side effects can be minimized and efficacy can be maximized by targeting multiple aspects of prostate cancer. And fortunately, we have seen some combinations which have shown acceptable safety profiles so far.
Efficacy data, as I said, is preliminary, is quite modest with most of these agents. And I think moving these agents to earlier lines of therapies, when patients have better performance status, better immune systems, less prevalence of visceral metastasis—I think they may be more effective. Or we can use biomarker-based selection of these patients to enhance their responsiveness. So can we use PSMA PET scan for PSMA-targeting bispecifics and trispecifics? Or can we use PET scan for DLL3 expression to further include patients who are more likely to respond to DLL3-targeting agents? Fortunately, all these trials are in development, and we look forward to T-cell engagers changing the therapeutic landscape of prostate cancer in the near future.
Alicia Morgans: Thank you so much, Neeraj. That was really a fantastic whirlwind of a discussion of all of these different approaches. These cell-based therapies are both extremely exciting but also fraught with some challenges that I think we're going to need to consider as we move forward. And you touched on these sort of towards the end of your talk. I wonder if you could dig into a little bit more on the opportunities for us to really potentially better select patients, better support patients. How do we really make this come to fruition? You mentioned some approaches that we might take. Let's dig in there.
Neeraj Agarwal: Yeah. So if you look at T-cell engagers so far—bispecific, trispecific—there's no doubt, but for the STEAP1 targeting agent, the efficacy has been quite modest. And one of the reasons at least I can think of is the setting where T-cell engagers were used. So if you look at those trials, every single trial has included patients who have progressed on an ARPI and taxanes. And we know by the time we get to this point during the journey of prostate cancer, there's a high prevalence of visceral metastases, performance status is quite low, and the immune system has already been compromised because of years of prior therapies. So can we move these T-cell engagers upstream? I know that STEAP1-targeting T-cell engagers are being used in biochemical recurrence, being used in patients who have not really progressed on an ARPI or a taxane. So that is one solution I can think of.
The second challenge, as we just discussed, is that a T-cell engager by itself can only target one antigen. But prostate cancer is a heterogeneous disease. It's not like a clonal malignancy like acute lymphoblastic leukemia. So can we combine these T-cell engagers with other drugs which target other aspects of prostate cancer? And in this context, we are already seeing development of trials which are using a T-cell engager in combination with a B7-H3-targeting antibody-drug conjugate, or interleukin-2, or another ARPI, or immune checkpoint inhibitors. And of course, we can think about various other ways to further improve their efficacy.
Alicia Morgans: I completely agree. The other area where I'm hopeful, though, that we can continue to advance is how do we expand the population that can receive these agents? And right now some of the toxicities are challenging, even in some of our fittest patients. Do you see a time where we might be able to come up with strategies and perhaps supports—whether they're slower administration of treatment, or steroid supports, or other methods—to allow patients to get these treatments in an outpatient setting, in a less controlled setting where maybe even a broader population can ultimately get treatment with these agents?
Neeraj Agarwal: You are absolutely right. We have to come up with T-cell engagers which are not associated with high risk of cytokine release syndrome. And it will require a lot of focus on developing new classes or new generations of T-cell engagers. I think—I'm sure we will see an evolution of T-cell engagers—first generation, second generation, third generation. And I'm really hoping we'll get to a point where these therapies can easily be administered on an outpatient basis, which will also allow more frail, more older patients to receive these T-cell engagers.
And one aspect I did not discuss in my presentation was the significant burden on healthcare when we have to admit these patients to the hospital. It is not uncommon for us to not be able to find beds within the next two or three hours to admit our sickest patients. Often across the healthcare system in our country, we see hospitals are full. And to add to that burden by creating trials which require inpatient hospitalization is not going to allow many of our patients to receive these drugs. So ultimately, we'll have to develop T-cell engagers which have much fewer side effects, much less severe side effects, which will allow more patients to receive these drugs.
Alicia Morgans: I think that's a great message and a great goal for us as we move forward. So as we wrap up, what is your final message to listeners, your final thought on T-cell engagers?
Neeraj Agarwal: To conclude, T-cell engagers, in my view, are one of the most exciting classes of agents and have the potential to change the therapeutic landscape for patients with metastatic prostate cancer. I think the challenges are there, but I'm sure we'll come up with solutions—with novel combination regimens, novel drugs, novel T-cell engagers with less side effects—which will ultimately allow them to be delivered on an outpatient basis and to more patients who are frail, who are older, and who will be able to handle these agents better.
Alicia Morgans: Well, that is a wonderful closing thought and certainly really gives us hope for the future and a direction to proceed. So thank you so much for your review of an incredibly exciting but incredibly complicated topic. As always, I appreciate your expertise.
Neeraj Agarwal: Thank you very much for having me today.
Alicia Morgans: Hi, I'm so excited to be here today with Professor Neeraj Agarwal, who is joining me after a wonderful presentation at ESMO 2024, where he really explained to us how we should think about T-cell engaging treatments for prostate cancer. Thank you so much for your time, Neeraj. Please tell us a little bit about this.
Neeraj Agarwal: Thank you. It's a pleasure to be here. So T-cell engagers are emerging as a new class of drugs, which hopefully will bypass the limitations posed by the cold tumor microenvironment of prostate cancer. So let's look at the rationale for using T-cell engagers first.
As we know, MHC-TCR engagement and co-stimulation are required for T-cell stimulation in normal circumstances, as we can see here. However, MHC expression is downregulated in cancer cells. T-cell engagers bypass the steps needed for MHC-TCR-dependent T-cell activation by engaging with both CD3 receptors on T-cells and a tumor-associated antigen on cancer cells—the prostate cancer cells in this context—leading to T-cell-mediated killing of cancer cells.
We know that T-cell engagers have shown a lot of promise in hematologic cancers and were first approved for acute lymphoblastic leukemia. In the context of solid tumors, we just saw tarlatamab, which targets DLL3 antigen expressed on neuroendocrine small cell lung cancer, was approved based on promising objective responses seen in the Phase II DeLLphi-301 trial.
So coming back to prostate cancer, there are multiple tumor-associated antigens, as you can see here, which can be targeted by T-cell engagers.
So these are the four bispecific T-cell engagers which have been studied so far, and we do have preliminary data available. And that includes pasotuxizumab, acapatamab or AMG 160, JNJ-081, and LAVA-1201.
So all these were early-phase trials, dose escalation, dose expansion trials, where PSMA was targeted. And what we have seen so far is that PSA 50% responses have ranged from 7% to 32%. And we have seen some objective responses. And we have seen that most of these patients were heavily pre-treated, progressed on ARPI, taxane, and unfortunately, two of these drugs are not being developed further because of the onset of anti-drug antibodies. In the context of AMG 160, it is not undergoing further development, given the toxicities of cytokine release syndrome and the lack of antitumor responses which are durable. LAVA-1201 is still being tested, and we look forward to the data from the dose expansion phase in the near future.
One of the promising antigens I find is STEAP1, which was tested in an early Phase I or early-phase trial, as reported by Dr. William Kelly and team in Cancer Discovery very recently. And let's look at the rationale for developing T-cell engagers against STEAP1. So STEAP1 is associated with cancer cell proliferation, invasion, and epithelial-mesenchymal transition. And it's quite expressed in prostate cancer cells. As we can see here, 87% of patients express STEAP1 antigen.
So in this early-phase trial, a bispecific T-cell engager targeting STEAP1 was associated with quite promising PSA responses if you look at PSA 50% response in heavily pretreated patients. And just to let me—allow me to go back for a second. You can see here, half of the patients had visceral metastasis. Thirty-seven percent of patients had liver metastasis. In this patient population, to achieve a PSA 50% response in 50% of patients and a PSA 90% response in 30% of patients is quite remarkable. The good news was that although CRS was quite common in 72% of patients, it was quite manageable with dexamethasone, interleukin-6 antibody, which is tocilizumab.
Now go back—let's go to another T-cell engager targeting another antigen on cancer cells. And in this case, it is tarlatamab, which I just discussed. It targets DLL3, which is expressed on small cell lung cancer. But for us, for patients with prostate cancer, it can also target those patients who have neuroendocrine differentiated prostate cancer. And we do have some data in this context presented by Dr. Rahul Aggarwal, where we saw objective responses of 10% in these 40 patients. And there were higher responses in patients who had high DLL3 expression. So it looks like patients who had high DLL3 expression may have better responses to tarlatamab. Further studies are coming up, and we look forward to seeing the data of tarlatamab in neuroendocrine prostate cancer.
And fortunately, side effects were not that common. Even though 75% of patients had cytokine release syndrome, only one patient had grade three or more side effects. Neurotoxicity events, which are associated with T-cell effector cells, were also present in 12%. But again, fortunately, only one patient had grade four side effects.
And there's another class of T-cell engager known as trispecific T-cell engagers. These are associated—why they are trispecific—because they have a third binding domain which can be bound to or which can be used to target a new tumor-associated antigen, or which can be used to target another T-cell receptor, or which can be fused to human serum albumin, which can allow the extension of half-life of these agents, thereby allowing them to stay in plasma for a longer time and circulate longer. So in this context, we have seen two trispecifics, one targeting PSMA and one targeting DLL3.
And this is the summary data from these two trispecific T-cell engagers. HPN424 is no longer being developed in this trial, but HPN328, which is a DLL3 trispecific T-cell engager, is being developed further, and we look forward to seeing the data again in the near future.
And the story is not going to finish here. We are going to see more novel T-cell engagers, which are designed to target antigens beyond STEAP1 and PSMA, such as prostate stem cell antigen, KLK2, or immune checkpoints.
And so far what we have learned is that these are new therapies with novel mechanisms of action. Most have manageable safety profiles. However, antitumor activity has been quite subtle. And there are challenges which have been faced by these T-cell engagers, which include presence or onset of anti-drug antibodies, which can affect—compromise—the exposure to this drug, and cytokine release syndrome, which requires many of these patients to be hospitalized, which can strain the healthcare system, and also can increase the cost and inconvenience to the patients, in addition to being life-threatening if they are grade three or four and if they're not managed properly.
And this can be—we can go around these limitations by multiple ways, which include combining with novel agents, combining with... So both side effects. So we can combine them with novel agents at lesser doses, so that side effects can be minimized and efficacy can be maximized by targeting multiple aspects of prostate cancer. And fortunately, we have seen some combinations which have shown acceptable safety profiles so far.
Efficacy data, as I said, is preliminary, is quite modest with most of these agents. And I think moving these agents to earlier lines of therapies, when patients have better performance status, better immune systems, less prevalence of visceral metastasis—I think they may be more effective. Or we can use biomarker-based selection of these patients to enhance their responsiveness. So can we use PSMA PET scan for PSMA-targeting bispecifics and trispecifics? Or can we use PET scan for DLL3 expression to further include patients who are more likely to respond to DLL3-targeting agents? Fortunately, all these trials are in development, and we look forward to T-cell engagers changing the therapeutic landscape of prostate cancer in the near future.
Alicia Morgans: Thank you so much, Neeraj. That was really a fantastic whirlwind of a discussion of all of these different approaches. These cell-based therapies are both extremely exciting but also fraught with some challenges that I think we're going to need to consider as we move forward. And you touched on these sort of towards the end of your talk. I wonder if you could dig into a little bit more on the opportunities for us to really potentially better select patients, better support patients. How do we really make this come to fruition? You mentioned some approaches that we might take. Let's dig in there.
Neeraj Agarwal: Yeah. So if you look at T-cell engagers so far—bispecific, trispecific—there's no doubt, but for the STEAP1 targeting agent, the efficacy has been quite modest. And one of the reasons at least I can think of is the setting where T-cell engagers were used. So if you look at those trials, every single trial has included patients who have progressed on an ARPI and taxanes. And we know by the time we get to this point during the journey of prostate cancer, there's a high prevalence of visceral metastases, performance status is quite low, and the immune system has already been compromised because of years of prior therapies. So can we move these T-cell engagers upstream? I know that STEAP1-targeting T-cell engagers are being used in biochemical recurrence, being used in patients who have not really progressed on an ARPI or a taxane. So that is one solution I can think of.
The second challenge, as we just discussed, is that a T-cell engager by itself can only target one antigen. But prostate cancer is a heterogeneous disease. It's not like a clonal malignancy like acute lymphoblastic leukemia. So can we combine these T-cell engagers with other drugs which target other aspects of prostate cancer? And in this context, we are already seeing development of trials which are using a T-cell engager in combination with a B7-H3-targeting antibody-drug conjugate, or interleukin-2, or another ARPI, or immune checkpoint inhibitors. And of course, we can think about various other ways to further improve their efficacy.
Alicia Morgans: I completely agree. The other area where I'm hopeful, though, that we can continue to advance is how do we expand the population that can receive these agents? And right now some of the toxicities are challenging, even in some of our fittest patients. Do you see a time where we might be able to come up with strategies and perhaps supports—whether they're slower administration of treatment, or steroid supports, or other methods—to allow patients to get these treatments in an outpatient setting, in a less controlled setting where maybe even a broader population can ultimately get treatment with these agents?
Neeraj Agarwal: You are absolutely right. We have to come up with T-cell engagers which are not associated with high risk of cytokine release syndrome. And it will require a lot of focus on developing new classes or new generations of T-cell engagers. I think—I'm sure we will see an evolution of T-cell engagers—first generation, second generation, third generation. And I'm really hoping we'll get to a point where these therapies can easily be administered on an outpatient basis, which will also allow more frail, more older patients to receive these T-cell engagers.
And one aspect I did not discuss in my presentation was the significant burden on healthcare when we have to admit these patients to the hospital. It is not uncommon for us to not be able to find beds within the next two or three hours to admit our sickest patients. Often across the healthcare system in our country, we see hospitals are full. And to add to that burden by creating trials which require inpatient hospitalization is not going to allow many of our patients to receive these drugs. So ultimately, we'll have to develop T-cell engagers which have much fewer side effects, much less severe side effects, which will allow more patients to receive these drugs.
Alicia Morgans: I think that's a great message and a great goal for us as we move forward. So as we wrap up, what is your final message to listeners, your final thought on T-cell engagers?
Neeraj Agarwal: To conclude, T-cell engagers, in my view, are one of the most exciting classes of agents and have the potential to change the therapeutic landscape for patients with metastatic prostate cancer. I think the challenges are there, but I'm sure we'll come up with solutions—with novel combination regimens, novel drugs, novel T-cell engagers with less side effects—which will ultimately allow them to be delivered on an outpatient basis and to more patients who are frail, who are older, and who will be able to handle these agents better.
Alicia Morgans: Well, that is a wonderful closing thought and certainly really gives us hope for the future and a direction to proceed. So thank you so much for your review of an incredibly exciting but incredibly complicated topic. As always, I appreciate your expertise.
Neeraj Agarwal: Thank you very much for having me today.