January 2020 Edition Vol.11, Issue 1

Immunotherapy 2.0 at ASH: Improved CARs, Better Bispecifics

By Neil Canavan

Chimeric antigen receptor T cells (CAR-Ts, or simply, CARs), first approved by the FDA two years ago, are an extraordinary scientific achievement and a godsend for patients with hematologic malignancies that have no other treatment options – but there are problems: CARs are expensive, potentially harmful, difficult to manufacture, and prone to running out of gas.

Attempting to address these, and other CAR-related issues, were a multitude of clinical investigations presented at 2019 ASH. Highlighted herein are reports of an optimized CAR, an allogenic natural killer (NK) cell CAR, and, bypassing CARs altogether, two examples of the increasing popular modality of bispecific antibodies.

Mosunetuzumab

Mosunetuzumab is a bispecific antibody. Bispecific antibodies – also called T cell engagers – are protein constructs that target both T cells, usually through the molecule CD3, and a tumor-associated antigen, which in this case is CD20, located on B cells. Bispecifics “engage” T cells – any T cell, regardless of its specificity – and brings them into the proximity of tumor cells, which they then destroy. The poster child for this approach is a CD19-targeting drug called blinatumomab, approved in 2014 for the treatment of acute lymphoblastic leukemia (ALL).

Mosunetuzumab, a bispecific antibody that targets CD20, is currently being investigated for the treatment of non-Hodgkin’s lymphoma (NHL), as reported by Dr. Stephen Schuster, from the University of Pennsylvania’s Perelman Center for Advanced Medicine.

“When we approach unmet needs in medicine, we solve one problem, but often create another,” said Schuster. One problem is that not all patients respond to CAR-T therapy. Another, far more vexing problem is that it takes time to build a CAR.

“CAR-T cells can take three weeks to manufacture,” said Schuster, “Plus, it can take two weeks just to get the insurance approval before you can even go for apheresis (a procedure required for the manufacture of CARs).”

A wait of a month or two does not sound that long, but it’s an eternity if you are a patient with galloping disease. Bispecifics, on the other hand, are off-the-shelf drugs – readily available. “And to be able to use this immunotherapy approach rapidly is important.”

For the phase 1/1b dose escalation study of mosunetuzumab, Schuster reported on an interim analysis of 270 patients with relapse/refractory (R/R) B-cell NHL, treated in a step-up dosing fashion. “Step-up dosing mitigates cytokine release syndrome (CRS),” explained Schuster, “And this allows dose escalation to maximize therapeutic potential.” (CRS is a class effect of drugs that directly activate T cells.)

Patients were treated on a 21-day cycle until complete response (CR) was observed, or a maximum of 17 cycles was given. Endpoints for the study were identification of maximum tolerated dose, and best overall response rate (ORR).

Patients with prior CAR-T treatment within 30 days of study entry, or who had received an allogeneic stem cell transplant, were excluded.

Results for safety showed that 28.9% of patients experienced some level of CRS, with only three patients having a grade 3 severity. Grade 3/4 adverse events included neutropenia (21.8%) and anemia (8.9%). One grade 5 event occurred, due to pneumonia (it is unclear if this was drug related). Eight patients received treatment with the anti-Il-6 drug, tocilizumab, to resolve their CRS.

“T cell engaging therapies also have neurologic adverse events,” said Schuster, but of those observed in this trial – in 10 patients – all resolved within 3 days.

For the 124 patients evaluable for efficacy, an ORR of 37.1% was seen, with a CR rate of 19.4% (Figure 1).

Observed responses also included patients with aggressive lymphoma histologies who were refractory to anti-CD20 monoclonal antibody-based therapies (i.e. R-CHOP).

Interestingly, patients who had relapsed after prior CAR-T therapy also responded, with an ORR of 39%, with four patients achieving CR. Conversely, mosunetuzumab enabled follow-on CAR-T treatment, whereby one patient with R/R follicular lymphoma with rapid disease progression was stabilized prior to receiving a CAR.

“This one case shows the potential sequence of mosunetuzumab before CAR-T therapy, as opposed to trials where patients who were largely getting mosunetuzumab afterwards,” said Schuster.

Other efficacy results show that mosunetuzumab has the potential for use as a retreatment strategy.

“Four patients on this trial who achieved a CR with mosunetuzumab, and later relapsed, were retreated with this agent,” Schuster reported. “Three of the four had responses, with one CR – and this ability to retreat is something that we have not been able to do with the CD19 directed CAR-Ts, so this is a gratifying finding.”

“I think the future for this drug, and this off-the-shelf approach to exploiting cellular therapy is the direction we will be pursuing in the future.”

Further single-agent, and combination trials with this drug are ongoing.

Cells R Us: FT596

In keeping with the theme of immunotherapy products that are, A) off the shelf, and B) not CAR-T cells, progress was reported by Bob Valamehr, of Fate Therapeutics, for the successful manufacture of FT596, an allogeneic NK CAR product.

The advantages of using NK cells to fight cancer are currently under debate, but in general, NK cells have a broader activity than T cells, and represent less of a potential risk to patients when administered – this last part being particularly true if the NK cells are created de novo.

“At Fate we’ve been working on iPSCs, which is the starting material,” explained Valamehr. “These are pluripotent cells that can become any of the cell types in the body. With this, we can work at a single cell level to do precise engineering to create master cell banks of a uniform composition for homogeneous cell products.” Once done, these “iNK” cells – which are theoretically compatible with most any immune system – are then loaded up with targeting mechanisms in much the same manner as T cells.

FT596 is a CD19-targeted iNK CAR, enhanced with a CD16 Fc receptor to promote cell killing through the mechanism of antibody-dependent cellular cytotoxicity (ADCC), when FT596 is combined with therapeutic antibodies.

As reported at ASH, when tested in vivo in a murine model of ALL, FT596 demonstrated equivalent efficacy to that of CD19-targeted CAR-Ts, further, when combined with rituximab, tumor cells were effectively cleared in a CD19+/CD20+ Burkett’s lymphoma model.

So… great… but why were these preclinical data so impactful at ASH? (Fate’s stock shot up 45%.) Because, as mentioned, CAR-Ts are made-to-order, can only treat the patient that the T cells come from, and are very expensive. While Fate has yet to say what iNK treatment might cost, the price of anything comes down when manufactured in bulk, and this off-the-shelf approach using an iPSC cell bank means patients can be treated on demand.

And demand, it seems, will be high.

JNJ 5528

Demand is not always a good thing. When the data set for JNJ-4528 was first reported at 2017 ASCO under the name LCAR-B38M (the drug was then being developed in China by Legend Biotech, now part of Janssen) the results were so good – a ORR of 100%; nearly all 19 patients in the trial achieving CR –  there was a great demand to know how they did it. Yet, the details regarding patient selection, and treatment strategies were (oddly) not forth coming. Even CAR-T experts like Juno founder, Michel Sadelain, were left to wonder. “They couldn’t tell me anything.”

Fast-forward to 2019 ASH, and it seems the clinical (or corporate) haze has cleared, and prior efficacy results have been more or less validated.

JNJ-5528 is a “second-generation” CAR-T product, with a 4-1bb costimulatory domain, that targets BCMA, a molecule present on B cells in multiple myeloma.

“Multiple myeloma accounts for about 10% of all hematologic cancers worldwide,” said Dr. Deepu Madduri, Mount Sinai Medical Center, New York. “Despite advances in the last few years in multiple myeloma drugs, if you are a patient who has failed all approved therapies your median overall survival is less than one year.”

In the phase 1/2b CARTITUDE-1 study, R/R multiple myeloma patients with a median of five lines of prior treatment achieved an ORR of 100% (again), with 69% of those patients in CR (N=29). Further, 27/29 patients remain progression-free at a median follow-up of six months (Figure 2).

“These are very heavily pretreated patients,” said Madduri, “So getting early, and deep responses is amazing.”

As for safety, 27% of patients experienced CRS – almost all mild – except for one grade 4 CRS which turned into a grade 5 event. Other adverse events were typical of CAR-T treatment, and were transient.

As for explaining the prior, and current, stellar efficacy results seen with this therapy, “What we think differentiates this product is the preferential expansion of CD8+ central memory cell phenotype,” explained Madduri. “What that means is that CD8 cells are the ones killing your myeloma cells, but these central memory cells have a way of not getting exhausted as often, and therefore retain effector cell function.”

Regardless of the mechanism, the efficacy speaks for itself: the day before ASH began, the FDA designated JNJ-4528 as a Breakthrough Therapy.

Blinatumomab

Returning to the mechanisms employed by bispecific antibodies, the first-ever approved such construct, blinatumomab, was the subject of a phase III investigation in children, and young adults (AYA) in high, and intermediate risk first relapse after treatment for B cell ALL.

“Cure rates for children and young adults have improved dramatically over the years,” said Dr. Patrick Brown, of the Sidney Kimmel Cancer Center, Baltimore. “But relapse still occurs in roughly 15% of patients, and survival is poor after relapse.”

In that setting the only treatment option is to have the patient achieve a second remission with standard-of-care (SOC) chemotherapy, followed by a stem cell transplant – that is, if the patient survives the heightened risk for life threatening infections caused by the chemo.

“The object of this trial is to determine if subbing blinatumomab for intensive consolidation chemotherapy improves survival in this setting.”

The schema was straightforward – compare the bispecific to SOC in patients with early relapse, or late, high minimal residual disease after first-line treatment. All patients achieving remission would then go on to transplant (planned enrollment: N=222).

Once the trial was underway, the advantage of this proposed new strategy was readily apparent.

“After 208 patients were randomized, the trial was closed early when the independent data monitoring committee determined that the blinatumomab arm was superior,” said Brown.

In fact, with median follow of 1.5 years, treatment with blinatumomab resulted in a 20% increase in progression-free- survival as compared to chemotherapy, and further, overall survival was increased by 20% at 2 years (Figure 3).

“The improved survival with blinatumomab was likely due to two factors,” said Brown. “The first was that patients treated with blinatumomab were much more likely to have cleared residual disease in their bone marrow than patients treated with chemo. The second is that the serious adverse events (in particular, infections) were much lower than in the chemo arm.”

Both aspects meant that the patient was far more likely to go on to transplant (Figure 4). “And transplant is the treatment most likely to cure patients with relapsed ALL.”

After seeing the data, Robert Brodsky, director of the division of hematology at Johns Hopkins, was both brief, and blunt in his assessment: “This is a new standard-of-care.”

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