January 2019 Edition Vol.11, Issue 1

A Race Well Underway: CAR-Ts Overtake ASH

By Neil Canavan

To cover a lot of ground quickly, you need a car. To spill a lot of ink quickly, cover just a fraction of the CAR-T cell presentations at ASH 2018. To that end, and discussed herein, there is: longer-term follow-up data for chimeric antigen receptor (CAR) T cell products currently approved; approaches to optimize patient care and access to CARs; tweaks to optimize CAR-T cell efficacy with combinations and genetic tweaks to the CARs themselves; and the potential for universal adoptive cell therapy.

ELIANA Trial: Longer-term, follow-up pediatric patients with relapse/refractory ALL

In brief, the ELIANA study looked at pediatric patients with relapse/refractory (R/R) ALL treated with tisagenlecleucel (Kymriah, N=79). The data presented at ASH 2018 by Stephan Grupp, University of Pennsylvania, were an update to the registration trial and represented an additional 11 months of follow-up from previous reports. Investigators wanted to see how patients who initially responded were doing over time.

Turns out, they are doing well—of the 82% of critically ill patients that went into remission initially, 66% remain in complete remission at 12 and 18 months. “That longer-term follow up indicates that there are groups of patients for whom this therapy has the potential for long term disease control,” said Grupp. Further, overall survival at 18 months for all infused patients was 70% – which is an extraordinary finding for patients who had months, or even weeks to live at study entry (Figure 1).

 

JULIET Trial Update: Diffuse large B-cell lymphoma

Richard Maziarz, Oregon Health & Science Knight Cancer Institute, Portland, gave an update on the phase II JULIET investigation. First reported at ASH 2017, the data represent a median follow-up of 19 months. “The reason this is important is … as you move into 19 months, now you are looking at the natural history of this disease.”

JULIET focused on adult patients with R/R DLBCL. Primary endpoints were overall response rate (ORR), complete response (CR), partial response (PR), and as a secondary endpoint, overall survival (OS).

The ORR for JULIET was initially 54% for the entire cohort (this was a single arm study), with 40% of patients achieving CR. The update had more of the same, but “54% of patients who had a PR converted to CR, so the drug continues to work over time,” said Maziarz. This encouraging phenomenon is the exact opposite of how chemo or targeted cancer therapy works.

For all patients, regardless of response, the OS was 11.1 months. More impressively though, the median OS for patients in CR has yet to be reached (Figure 2).

 

Regarding safety, the incidence of cytokine release syndrome (CRS)—a hallmark of CAR-T therapy—was less in this disease setting than in ALL.

“This is the beginning of the end,” said Maziarz, meaning—it works—genetically engineered T cells, a living drug, works. “What we are doing now is investigating ways we can build on the first-generation T cell therapies.”

CAR Tune Ups

There are three distinct ways of improving on CAR-T therapy: expanding access/efficacy through patient selection; adding other drugs to work in combination with CARs; and expanding on the original CAR-T cell design.

Rawan Faramand, a clinician at Moffitt Cancer Center, where a new service has been established to treat CAR-T patients, observed in her small study of patients receiving Yescarta that certain point of care cytokine measures could predict the onset of CAR-T-related adverse events and that those events precipitated poorer outcomes (N=20). Biomarkers of note included elevated levels of IL-6, and ANG1/2 ratios at day one that indicate the potential for severe CRS, and potentiate early intervention in these patients.

To expand the pool of CAR-T patients who are eligible to be treated, Dahlia Sano, of MD Anderson Cancer Center looked at elderly R/R DLBCL patients (>65) being treated with Yescarta. Sano found the same response rates in the elderly as those seen in younger patients, and this, with roughly the same side effect profile. Sano concluded, “I hope this increases access in a population with a high unmet need.”

Add Ons: Ibrutinib; Checkpoints

While there are over a thousand trials planned, or already initiated using checkpoint inhibitors in combination, combinations with CARs are just now underway. One of the more promising add-ons seems to be the immune-modulating drug, ibrutinib, currently approved for CLL, as well as several types of lymphoma.

Jordan Gauthier, of the Fred Hutchinson Cancer Center, Seattle, reported on the use of ibrutinib in combination with JCAR014, yet another CD19 targeted CAR-T product. JCAR014 had already scored some points in the CLL setting, but there was plenty of room for improvement, according to Gauthier, thus, the addition of ibrutinib.

Previous work suggested that ibrutinib may prevent rapid tumor progression (giving CARs time to work); it mobilizes CLL cells from the lymph nodes into the blood (allowing CARs to more easily find them) and it decreases CAR toxicity by perhaps chipping away at some of the tumor burden before CARs fully engage.

This retrospective analysis looked at two cohorts of CLL CAR-T patients; one group had no concurrent ibrutinib administration (n=23), the other did (n=18).

The response rate in the concurrent cohort was 83% vs 65% for those who received CARs without ibrutinib. Further, no patient developed a severe form of cytokine release in the concurrent ibrutinib group vs 25% for the comparator. Next, these data will seek validation in the prospective, TRANSCEND-CLL trial, currently enrolling.

Checkpoint Please

This next observation grew out of follow-on work by Shannon Maude, et al, at Children’s Hospital of Philadelphia, as she attempted to rescue Kymriah-treated, pediatric ALL patients who showed early signs of CAR-T loss, or lack of response. “Our hypothesis was that T cells upon activation may become exhausted through activation of checkpoint pathways,” said Maude. Solution: try a checkpoint inhibitor.

It was a partial success. For patients who had partial, or no response to CAR-Ts, the treatment was ineffective. In the setting of poor CAR-T persistence, three out of six patients responded. “We saw that some patients who were reinfused with a CAR-T cell product followed by infusion with anti-PD1 had a return of B cell aplasia (a sign of CD19 CAR-T activity), and had sustained CRs— showing continued persistence of their CAR T cells.”

Importantly, the added drug did not significantly add to toxicity.

To be sure, while these findings are important, “Larger studies are needed to determine if there is a major role for checkpoint inhibitors in this setting.”

Next Year’s Models

To address the issue of T cell exhaustion, and by extension, CAR-T toxicity, the laboratory of Michel Sadelain, at Memorial Sloan Kettering, NY, NY has developed a CD19 CAR with surface expression of the immune stimulator, 4-1BB. The idea being that by expressing 4-1BB ligand on the surface of the CAR-T it can engage not only the modified CAR-T cells but can also engage the endogenous unmodified T cells of the patients to produce a higher immune response against cancer cells, explained by Jae Park, of MSKCC.

This tweak was tested in a first-in-human, dose-ranging trial in a cohort of patients with R/R NHL, and CLL, reported here with a follow-up of 4.8 months (N=29). Of the proposed range of doses, “We hypothesized that the cells would to be more potent (than first-generation CARs), and so perhaps we could use fewer T cells to generate similar, if not superior tumor efficacy, as well as reduced safety profile because we’re using a lesser dose.”

Results suggest that this is indeed the case. The optimum dose identified was 3 million cells/kg as opposed to 30 million cells/kg for approved CAR-Ts. Responses in DLBCL at this dose level were 78% (CLL patients responded at a 20% rate, but this was at the lower CAR dose).

“In DLBCL patients, most of the CARs were durable,” said Park, “and five out of seven remain in CR, with the longest on-going response of about one year.” Of note, and quite possibly due to the fewer cells used, there was no severe CRS observed, and no grade 4 neurotoxicity.

Dual Targeting

To address the issue of CD19 antigen escape – the mechanism by which tumor cells can evade the CD 19 CAR, a CD19/CD22 dual targeting CAR is now on the road.

“In the ELIANA trial there was a promising 81% overall response rate at month three,” said Nasheed Hossain, of Loyola University, Chicago. “But the 12 month event-free survival is 50%.” Of those who relapsed, 15 of 16 patients no longer express CD19. (Antigen loss occurs in DLBCL as well.)

The new CD19/CD22 CAR was taken for a phase I test drive in adults with R/R B cell malignancies (N=9).

Results showed no serious drug-related toxicities, and no dose-limiting toxicities. As for observed efficacy, there was a 60% response rate in DLBCL patients at three months, with one ongoing CR. Of two evaluable ALL patients, there was one CR and one PR at day 28.

An expansion cohort at dose level 2 (3×106/kg) is planned for Q1 2019.

FATE

Finally, CARs are super expensive, and that’s a problem. The most high-tech way to bring prices down would be to have off-the-shelf, allogeneic CAR-T cell products. Several companies are chasing this grail, such as Allogene, Cellectis, Servier, but their approach is to engineer mature donor cells, which is problematic. As FATE would have it, the easiest workaround to avoid potential immunogenicity from donor cells is to engineer cells from the get-go, use induced pluripotent stem cells (iPSCs) that can be manipulated at the single cell level, and then expanded.

FATE’s initial foray into iPSCs produced NK cells, a cell that bridges the innate and adaptive immune systems and is capable of detecting cancer. The development program for their most advanced NK product is FT500—an allogeneic off-the-shelf NK cell cancer immunotherapy derived from a clonal master iPSC line. For this investigation, FT500 will be combined with anti-PD1s in a basket trial of solid tumors.

FATE is currently working with CAR-T pioneer, Michel Sadelain, to develop a line of allogenic, off-the-shelf, CAR-T cells and Wall Street loves it. As of the FDA announcement, FATE, for the first time in company history, achieved a market cap of $1 billion.

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