Inside Mustang Bio's Phase 1/2 Clinical Trial Of MB-106

By Erin Harris, Editor-In-Chief, Cell & Gene
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Mustang Bio recently reported a favorable safety profile suitable for outpatient treatment and a high complete response rate, including patients with Waldenstrom macroglobulinemia and those who received prior CD19-directed CAR T therapy. The company expects to dose the first patient in a multicenter clinical trial this quarter. I caught up with Manuel Litchman, M.D., President & CEO, Knut Niss, Ph.D., CTO, Bruce Dezube, M.D., SVP & Head of Clinical Development at Mustang Bio to better understand their Phase 1/2 clinical trial of MB-106 as well as the company’s other ongoing clinical trials, and more.

Explain Mustang Bio’s updated interim data from the ongoing Phase 1/2 clinical trial of MB-106, a CD20-targeted, autologous CAR T cell therapy for patients with relapsed or refractory B-cell non-Hodgkin lymphomas (“B-NHLs”) and chronic lymphocytic leukemia (“CLL”). 

The updated interim data begin to address some of the most important questions that investors have had since Dr. Shadman first presented data from this ongoing Phase 1/2 clinical trial of MB-106 at ASH 2020:

1. Can the safety profile of no CRS or ICANS ≥ grade 3 be sustained as more patients are enrolled and as different CD20+ histologies are explored?  The answer so far is yes, with now 20 patients enrolled with a variety of histologies:
   1. Follicular lymphoma (FL; N=18)
   2. Mantle cell lymphoma (MCL; N=2)
   3. Chronic lymphocytic leukemia (CLL; N=1)
   4. Diffuse large B cell lymphoma (DLBCL; N=2)
   5. Waldenstrom macroglobulinemia (WM; N=2)
2. The results in follicular lymphoma have been impressive and sustained with the enrollment of more FL patients – but can these results be replicated in other indications – in particular in indications where CAR-Ts have not yet been approved?  This is a critical question, since Mustang needs a differentiated registration strategy in order to compete against the approved and emerging adoptive cell therapies.  The data clearly show responses in 3 major indications where we hope to initiate pivotal non-randomized Phase 2 clinical trials once dose escalation is complete in 2023:
   1. CLL:  So far one patient has achieved minimal-residual-disease-negative status, with complete response (CR) &GT 1 year, which greatly increases the probability of long-term remission.
   2. Disease relapsed from treatment with CD19-directed CAR-T therapy:  So far we have seen two such patients, and both responded to treatment – one patient with FL who achieved a CR and the other with DLBCL who achieved a partial response (PR).  It should be noted that, as a result of the persistence of CAR-T cells in so many patients on this trial, we have seen 5 PRs deepen to CRs – and none of these has relapsed.
   3. WM (a special subset of indolent lymphoma):  So far we have seen two such patients, and both responded to treatment – one patient with a PR and the other with a PR initially that later deepened to a CR.  Again, with respect to the PR, we await the next response assessment to determine if the response has deepened to a CR.  We have filed a request with the FDA for Orphan Drug Designation for this disease.

It should be noted that the Phase 1 design of Mustang’s 6-center trial is such that there will be 3 independent dose escalation arms, which will ensure that we do not enroll a preponderance of FL patients, as is currently happening in the Hutch trial:

1. Aggressive lymphoma, which we expect will be DLBCL patients who have relapsed from CD19-directed CAR-T therapy, since many prescribers may be reluctant to treat with an investigational CAR-T when there are several approved CAR-Ts with good efficacy (though safety continues to be inferior to MB-106 safety, and only 40% of patients experience long-term remissions, leaving 60% to require additional therapy at a later point in time.
2. Indolent lymphoma, which we expect will enroll a disproportionate number of WM patients, since we have selected a center that specializes in treating WM patients.
3. CLL

3. What about durability?  Follow-up has been relatively short so far. So far we have 5 patients who have achieved a CR sustained for &GT1 yr – a rather striking early result.  And 4 other CRs are just shy of the 1-year mark.  Looking at the 6-month CR rate, it is 75% - which is highly competitive vis-à-vis other adoptive cell therapies.
4. Other adoptive cell therapy programs – such as the allogeneic CAR-Ts and the CAR-NKs – have had to resort to multiple dosing to achieve durability.  Can Mustang’s program remain “one and done?”  The answer is a resounding “yes.”

It’s been published that there is possibility of outpatient administration of this therapy. When will timeframe be known, and how will outpatient administration impact patients with B-NHLs and CLL?

We believe that we have already shown the possibility of outpatient administration of MB-106 therapy.  To date, all the events of cytokine release syndrome and neurotoxicity have been low-grade – Grades 1 and 2. This favorable safety profile should make MB-106 therapy suitable for mostly outpatient therapy.  Outpatient treatment has two major advantages:

1. First, patients can recover in the comfort of their own home. Instead of remaining in an uncomfortable bed and sterile room, they can find a comfortable position on their favorite couch, chair or bed and enjoy activities of their choice. They can even enjoy their own food rather than hospital food.  This is on top of the incremental patient convenience resulting from fewer and shorter admissions post-therapy due to the absence of ≥ Grade 3 episodes of cytokine release syndrome and neurotoxicity that are seen with the currently approved CAR-T therapies.
2. Second, outpatient procedures cost less than comparable inpatient procedures. Inpatient admissions are very expensive.  Patients can realize significant savings by recovering at home instead of in a hospital room. In many cases, the difference between outpatient and inpatient care is thousands of dollars both to the patient and to the insurers. This is on top of the savings realized from fewer and shorter admissions post-therapy due to the absence of ≥ Grade 3 episodes of cytokine release syndrome and neurotoxicity that are seen with the currently approved CAR-T therapies.

The release states that CAR T expansion was observed across all dose levels. Explain in detail what this means for the patient. 

This is a very important point. We aim to produce a specific dose of CAR-T cells. However, transduction efficiency and cell expansion can vary from lot to lot. Even with a consistent manufacturing process, such variations are expected to occur. The good news is that we have been able to expand the CAR-T population across all dose levels in all patients to date despite these expected variations.

Walk us through Mustang Bio’s other ongoing clinical trials. 

In addition to the MB-106 program, the 2 programs that we are most excited about are the XSCID (bubble boy disease) gene therapy program and the combination CAR-T + oncolytic virus program for glioblastoma & anaplastic astrocytoma – highly malignant brain tumors.

1. The XSCID program is two distinct programs using the same lentiviral vector to insert a normal copy of the mutated gene causing severe immunodeficiency.  Each program has its own Rare Pediatric Disease designation, so that each one will be eligible for its own pediatric rare disease voucher at the time of approval, which can then be sold for $100M+.
   1. MB-107:  Treatment of newborns, who will die of overwhelming infection by age 1 if not treated – with standard of care currently allogeneic stem cell transplant (allo SCT). This is a 3-center investigator-IND trial being led by St. Jude Children’s Research Hospital in collaboration with Seattle Children's Hospital & UCSF Benioff Children's Hospital.
   2. MB-207:  Treatment of patients who have undergone allo SCT, but who are experiencing decline in T cell number & function, gradually leading to increasingly aggressive infections & eventually requiring a second allo SCT. This is a single-center investigator-IND trial being conducted at the NIH/NIAID.

These 2 programs are largely de-risked, having achieved an excellent safety profile across almost 40 patients and 100% reconstitution of T cells without any subsequent loss of T cell function or number.  With Phase 1 complete for each of these programs, Mustang intends to initiate pivotal non-randomized Phase 2 multicenter trials under its IND in 3Q2022 for MB-107 and in 1Q2023 for MB-207.

Finally, at the annual meeting of the American Society of Gene & Cell Therapy in May, we look forward to seeing the first update of data from the MB-107 trial since the American Society of Hematology annual meeting in December 2019.

2. The combination CAR-T + oncolytic virus program for glioblastoma and anaplastic astrocytoma will be our boldest and most innovative clinical program.  It will be the first industry-sponsored trial to combine these 2 therapeutic modalities for the treatment of any disease, and it rests on a solid foundation of data partially presented at AACR 2022:
   1. A 54-patient completed Phase 1 trial in recurrent grade III/IV malignant gliomas at City of Hope, where complete responses of 7.5* and 31+† months, respectively, were observed in the only 2 “hot” tumors, as characterized by a high infiltration of CD3+ T cells. 
   2. An ongoing Phase 1 trial in recurrent glioblastoma, where the investigator at the University of Alabama showed histologic evidence in a single patient that the HSV-1 oncolytic virus was able to reshape the tumor microenvironment and turn the tumor hot.

The hypothesis, then, is that we can turn patients’ tumors hot with intratumoral injections of the oncolytic virus, then follow it with multiple sequential doses of IL13Rα2 both into the cavity of the resected tumor recurrence as well as into the ventricular space, as COH has already done in its completed phase trial.

* Brown CE et al. NEJM. 2016;375:2561-2569..

†Brown CE. First Annual Conference on CNS Clinical Trials, October 1, 2021.

What might the CGT sector expect from CAR T cell therapies in the next few years?

We should expect several important developments in the CAR-T field over the next few years. For one, since efficacy of CAR-Ts in the solid tumor setting has been so far unsatisfactory, several new approaches underway now or anticipated in the near future will shed light of how to approach solid tumors with CAR-Ts. For this, combination therapies will be a key to a better understanding of CAR-T function in this setting. While checkpoint inhibitors are already studied in combination with CAR-T therapy, novel approaches such as using an oncolytic virus to turn tumors “hot” (causing infiltration of resident T-cells) will further drive the understanding of CAR-T function in the solid tumor space.

Furthermore, now that commercial CAR-T therapies are available with thousands of patients treated, one can be hopeful that the understanding of what drives efficacy of a CAR-T will greatly advance, leading ultimately to even better CAR-T products. Finally, thanks to new technologies we can expect a significant reduction in cost, allowing for a broader patient population to benefit from these therapies.