TriTAC: ASH 2022 Al-Ola Abdallah Updated Interim Results HBN217

By Al-Ola Abdallah, MD

What are the updated interim results from the HPN217 (Tri-specific T Cell Activating Construct [TriTAC®]) clinical trials in TRiTAC targeting BCMA for RRMM Patients in therapeutic T-cells? Today we're gonna talk a little bit about HBN217 (Tri-specific T Cell Activating Construct [TriTAC®]), which is a TriSpecific T-cell activating construct and relapse refractory myeloma. And this type of treatment is designed for a phase 1 trial to evaluate the safety, tolerability, pharmacokinetics, and activity of this treatment. The mechanical action of this drug, it has three domains that focus on BCMA, which is present in myeloma cells. And the CD3, which is a T-cell engager and a third domain against albumin to improve the half-life extension.

And that kind of forces the T-cells to attack the myeloma cells and cause cell death. And what we are doing here is evaluating, patients who received the HBN217 in Relapsed/Refractory Multiple Myeloma (RRMM), who receive at least 3 lines of therapy and were triple exposed to 4 different classes of anti myeloma therapies that include immune monitory drugs proteasome inhibitors and monoclonal CD38. Some patients were prior exposed to the same target (cells) therapy that we used, like BCMA and they were actually involved in this type of treatment.

What is the standard of care for patients with RRMM?  

The standard of care so far is we don't have any randomized trial for those patients who are heavily treated. But commonly now we're seeing BCMA targeted therapy like CAR T and other BCMA targeted therapy that enrolled and that are receiving this treatment. Why does it matter? To use this type of treatment the HBN217? Because Relapsed/Refractory Multiple Myeloma (RRMM) is still incurable even with these treatments so we still need more options of therapy. We don't have any alternatives after the patients actually progress on the any of the recent opt treatments.

So this can actually be adding more benefit for the treatments (for target cells). In addition to that also the safety, I think that's also a very important thing that we're hoping that we need more treatments that are more safer, less toxic, and more convenient for myeloma patients.

The trial design is a phase 1 trial that actually involved to evaluate the dosages of the HBN217 started with a small dose, and there was 2 phases in that design, the fixed dosage that they used, the similar dose from day 1 like weekly, 2.15 and 2.86. And then after that, there was a second attempt to increase the dosages 8 times more, and which we call the step dose.

The designation of that was to evaluate, of course the tolerance first and how effective the treatment is. And when we evaluated those patients who got the fixed dose, we found out 49% of them got cytokine release syndrome, all of them were grade 1 and 2, however, when we moved on to the step dose, which we started with a smaller dose, 2.15 and lower, and we increased the dose up to 12 and 24 milligram, we found out that cytokine syndrome went down to 29%.

Most of them were grade 1 and 2 we didn't see any grade 3 for these patients. And also we saw the efficacy have improved to 77%. So we believe that, type of fix step dose helped a lot to increase the dosage without any issues with the tolerance that we solve for these patients.

One more important thing is that for these patients that who receive it, although they are all triple exposure for the 3 different drugs 78% of them were triple refractory myeloma and 48% were pinta refractory, 20% were exposed to the BCMA and target (cells) therapy, which means that these patients were actually heavily treated for treatment.

The response rate, 77% was impressive but the grade the the toxicity of cytokine release syndrome was about 29% in the higher dose, in the step dose, also with all of them not grade three toxicity. We did not see any ICANS (Immune effector cell-associated neurotoxicity syndrome) any neurological abnormal movements that happen with that. So that's like very important to see that these patients receive a treatment that's effective and also well tolerated in that regard.

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What is TriTAC?

In the fight against cancer, T cell engagers or T cell-engaging bispecific antibodies are a new treatment technique. T cell engagers are synthetic proteins that reroute T lymphocytes to attack specific tumor cells. They function as adaptors that temporarily link T lymphocytes with their targets for the redirected lysis of tumor cells.

T cell engagers, unlike most other immunotherapies, allow T cells to bind to tumor-associated antigens. Thus, redirected lysis by T cells is independent of T cell receptor (TCR) specificity and MHC expression detection. Loss of MHC expression is a common way in which cancer cells avoid T cell identification.

In clinical trials, the bi-specific T cell engager has demonstrated remarkable therapeutic potential for the treatment of hematological cancers such as acute lymphoblastic leukemia (ALL).

With its proprietary TriTAC (Tri-specific T Cell Activating Construct) format, Harpoon is advancing this modality.

As an off-the-shelf T cell therapy, this unique class of T cell therapies aspires to achieve higher efficacy in penetrating solid tumors.

TriTACs, which consist of three binding domains, are intended to have an extended serum half-life and to be approximately a third the size of a monoclonal antibody.

What are some of the common questions you receive about the study?   

So far, the most common questions they were asked about the degree on the grade of the cytokine release syndrome. You know how it was very low in the higher dose. Some of them ask if we have used Tocilizumab as a prophylaxis, which we did not use in this group. Only 6% of these patients receive it after they got either grade 1 or 2 CRS, so it's a very small percentage of patients.

But I think that was the commonest question that we asked about that, of course, the second commonest question we ask about the infection rate in these patients, which is similar to other BCMA targeted therapy that have a higher infection rate, commonly pneumonia, upper respiratory infection, urine tract infection that we saw in these patients.

What are your final thoughts about this study?  

Many things about it, the efficacy of this treatment is really impressive, about 77% in this high risk. And we're talking about single agent treatment (in these clinical trials). The scheduling, and the dosing is still going to be optimized.

The purpose here is that we're moving to, instead of doing it weekly to every other week, and that's where we wanna make it convenient for patients, hopefully to see a better response rate and better efficacy as well in the future, we are seeing a longer duration of response for patients who are following up.

We are hoping that this will continue also, by time and to be a drug that's available off the shelf for all myeloma patients. 

Al-Ola Abdallah, MD - About The Author, Credentials, and Affiliations

The American Board of Internal Medicine has conferred a sub-certification on Dr. Al-Ola Abdallah in the specialties of hematology and medical oncology. At the University of Arkansas for Medical Sciences, an individual successfully completed a fellowship. His medical degree was from the University of Jordan, and he completed his residency at the University of Oklahoma at Tulsa College of Medicine. Both institutions are in the United States. He is currently at the KU Medical Center, University of Kansas.

Reference

Harpoon Therapeutics - TriTAC – T cell engagers for solid tumors. Harpoon Therapeutics, 2022