Targeting PSMA in Advanced Prostate Cancer - Episode 10

Future Directions of BiTE and CAR T for mCRPC

April 29, 2021
Ulka Vaishampayan, MD

,
Oliver Sartor, MD

A look toward the future development of bispecific T-cell engages (BiTEs) and CAR T-cell therapy for metastatic castration-resistant prostate cancer (mCRPC).

Ulka N. Vaishampayan, MD: There are other ways of engaging PSMA [prostate-specific membrane antigen]. Some of those are the T-cell or cellular therapies. For instance, there is the Regeneron compound, REGN 5678, which is a bispecific antibody, or a T-cell engager that binds to PSMA and CD28 on the T-cells and creates this activation of the immune system directed exactly at the PSMA-expressing cells—the prostate cancer cells.

That has reported some preliminary positive results, but most of these are at a much earlier phase compared with the radioligands that we discussed. But the imaging part is there to first find these patients who have the predominant PSMA-expressing tumors and then treat them with some of these novel immunotherapies.

The other is a PSMA bispecific T-cell engager called pasotuxizumab, which is also in early development. So far, the maximum-tolerated dose is being determined in an early phase 1 trial, but it’s showing preliminary promise of efficacy against metastatic CRPC [castration-resistant prostate cancer].

Amgen has a compound, AMG 160, which is also a bispecific T-cell engager, or BiTE, that binds on PSMA and CD3 on the T cells to activate the T cells. The advantage of AMG 160 seems to be that it’s relatively longer acting and has an extended half-life. We’ll have to stay tuned and wait and see if any of these make it to the approval setting and prove better and better efficacy in the long term.

Clearly, the immunotherapy could be then combined with radiation and sequenced after the radioligand therapies. There are lots of combinations to look forward to in the future.

Oliver Sartor, MD: Ulka, I wonder if you could mention a little about the toxicities. That has been a concern, particularly at this point, about the inpatient obligation for this type of therapy. 

Ulka N. Vaishampayan, MD: I agree. CAR [chimeric antigen receptor] T cells and a lot of these BiTEs were first developed in the lymphoma malignant hematology tumors. We’re now seeing that applying those kinds of techniques to older adults with comorbid conditions and the prostate cancer population is going to be somewhat challenging. The toxicity has to be taken into account. Patients have to be monitored very closely. There is the potential for the cytokine storm. Close monitoring using pressors and using a lot of immunosuppressant agents afterward because of the immune-related adverse events is key. If they do give remarkable response rates in efficacy, it may well be worthwhile. We probably will have to carefully select patients who can tolerate those kinds of toxicities with these treatments.

Going forward, the other modality is the CAR T cells. CAR T cells have shown remarkable 80% or 90% response rates in lymphomas, etc. The same technology is being utilized and evaluated in solid tumors like prostate cancer using PSMA as a target. These are very early data with phase 1 dose escalation studies ongoing, but so far it looks like patients are able to tolerate it without a lot of toxicity. Stay tuned for more PSMA-directed techniques, both immunotherapy, radioligands, etc, and there is the potential for more to expand on what we’re seeing so far.

Oliver, do you have any last remarks or any more things to comment on?

Oliver Sartor, MD: It’s a remarkable time in prostate cancer drug development. We’re moving forward fast in a lot of ways. PSMA is probably the most-studied target in clinical trials today, whether it’s immunotherapy or a variety of radiopharmaceuticals. In addition, we have the imaging implications of being able to use PSMA PET [positron emission tomography].

This is going to be dominating the conversation over the next 5 to 10 years. Maybe 10 years is a bit too far, but over the next 5 years, I see many manuscripts and studies with these compounds entering clinical practice in a very pragmatic way. Patients are going to be better for that intervention. They’re going to be better off because of the PSMA-targeted therapies and the PSMA imaging. That’s what we really want to do: improve patient care in the first place.

Ulka N. Vaishampayan, MD: Absolutely. That’s a perfect note to end on: looking at patient care and improving outcomes for our patients. This has been an extremely informative discussion. Thank you, Dr Sartor, for this insightful discussion. A huge thanks to our audience for watching this Targeted Oncology™ presentation on precision medicine. We hope you found this discussion to be useful and educational. Thank you.

This transcript was edited for clarity.