Startseite Kongressberichte & Archiv AACR Annual Meeting 2018, April 14-18, Highlights presented at the Press Conference Monday, April 16

Monday, April 16, 2018

Alice T. Shaw, MD, PhD, co-chair of the AACR Annual Meeting Clinical Trials Committee and director of the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center, will moderate a press conference highlighting the following research:
 

 

KEYNOTE-189 Met its Dual Primary Endpoints of Overall Survival and Progression-free Survival

CHICAGO—Patients with newly diagnosed metastatic non squamous non-small cell lung cancer (NSCLC)who received pembrolizumab (Keytruda)plus chemotherapy had significantly longer overall survival (OS) and progression-free survival (PFS)compared with those who received chemotherapy alone, according to data from the phase III clinical trial KEYNOTE-189, presented at the AACR Annual Meeting 2018, April 14-18.

This study is being simultaneously published in The New England Journal of Medicine (see bottom of page).

“The long-term survival of patients with advanced NSCLC remains poor and the standard of care for most patients is chemotherapy, which affords a survival benefit measured in months,”said Leena Gandhi, MD, PhD, associate professor in the Department of Medicine and director of Thoracic Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health.

In May 2017, the U.S. Food and Drug Administration approved pembrolizumab plus pemetrexed and carboplatin-based chemotherapy as first-line treatment for patients with advanced nonsquamous NSCLC based on data from the phase II cohort G of the KEYNOTE-021 study, but it was not widely adopted in the absence of positive results from a phase III study, Gandhi explained. “Further, the phase II study did not initially demonstrate a survival benefit,” she said.

“Results from KEYNOTE-189 are practice-changing,” noted Gandhi. “This phase III trial demonstrated an improvement in overall response rate (ORR), PFS, and OS across all groups of patients, irrespective of PD-L1 expression, halving therisk of death, which is an unprecedented effect of therapy in the first-line setting for advanced nonsquamous NSCLC without EGFR or ALK alterations.”

KEYNOTE-189is a randomized, double-blind, phase III study in patients with metastatic nonsquamous NSCLC who received no prior treatment for metastatic disease. Patients (616) were randomized, 2:1, to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab (test arm) or placebo (control arm). Patients were stratified based on PD-L1 tumor proportion score (<1 percentor ≥ 1 percent), among other factors.

After a median follow-up of 10.5 months, median OS was not reached in the test arm,versus 11.3 months in the control arm. Compared with patients in the control arm, those in the test arm were 51 percent less likely to die, and those in the high PD-L1 scoregroup were 58 percent less likely to die.

Median PFS was 8.8 months for the pembrolizumab arm, versus 4.9 months for the control arm. Patients were allowed to crossover to receive pembrolizumab if they progressed on the control arm. “Despite a 50 percent crossover rate, there was still a very clear survival benefit, suggesting that combination therapy upfront may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness,” Gandhi said.

“Toxicities were asexpected other than anincrease in the rate of acute kidney injuryin the pembrolizumab arm (5.2 percent, versus 0.5 percentin control arm), ”Gandhi added. Discontinuation of all treatment because of adverse events was 13.8 percent in the test arm, versus 7.9 percent in the control arm. Immune-related adverse events occurred in 22.7 percent of patients in the test arm, versus 11.9 percent of patients in the control arm.

A limitationofthe studyis that it was not designed to assess whether those with high PD-L1 expression benefited from pembrolizumab alone versus pembrolizumab plus chemotherapy, Gandhi noted. In addition, “The control arm did not perform as well as some historical controls, but this was a rigorous randomized study which did show a clear difference between the two arms,”she said. This study was sponsored by Merck. Gandhi has served on scientific advisory boards for Merck, Genentech/Roche, Syndax, Ignyta, and AstraZeneca, and has obtained research funding from Merck.

 

L. Gandhi et al. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. Abstract CT075
 
Background: The premise that chemotherapy and immunotherapy may provide greater benefit than pembro or chemotherapy alone was supported by KEYNOTE-021 cohort G, in which pembro + pem + carboplatin significantly improved ORR and PFS over pem + carboplatin in patients (pts) with advanced nonsquamous NSCLC. We present results of the KEYNOTE-189 study of pembro + pem-platinum vs placebo + pem-platinum as first-line therapy for metastatic nonsquamous NSCLC.
 
Methods: Pts with previously untreated stage IV nonsquamous NSCLC, no EGFR or ALK alteration, and ECOG PS 0-1 were randomized 2:1 to 4 Q3W cycles of pembro 200 mg or placebo + pem 500 mg/m2 + carboplatin AUC 5 or cisplatin 75 mg/m2 followed by maintenance pembro or placebo + pem. Randomization was stratified by PD-L1 tumor proportion score (TPS; <1% vs ≥1%), platinum agent, and smoking status. Response was assessed by RECIST v1.1 per blinded, independent central review. Pts in the placebo arm with verified PD could crossover to pembro monotherapy if eligible. Primary end points were OS and PFS in the ITT population. Prespecified superiority boundaries at the first interim analysis were one-sided P = .00128 for OS and .00559 for PFS.
 
Results: 616 pts were randomized: 410 to pembro + pem + platinum (“pembro arm”), 206 to placebo + pem + platinum (“placebo arm”). 76.5% of treated pts in the pembro arm and 66.8% in the placebo arm received ≥5 cycles of pem. 88.1% of enrolled pts were current/former smokers, carboplatin was chosen for 72.2%, and 63.0% had TPS ≥1%. As of Nov 8, 2017, median follow-up was 10.5 mo (range 0.2-20.4), and 33.8% in the pembro arm vs 17.8% in the placebo arm remained on treatment. In the placebo arm, 67 pts crossed over in-study to pembro and 18 received anti-PD-(L)1 therapy outside the study (effective crossover rate: 41.3% in the ITT population, 50.0% when pts still on treatment excluded). Pembro + pem + platinum, improved OS (HR 0.49; 95% CI 0.38-0.64; P < .00001) and PFS (HR 0.52; 95% CI 0.43-0.64; P < .00001) over placebo + pem + platinum. Median OS was not reached with pembro and was 11.3 mo with placebo. Median PFS was 8.8 mo vs 4.9 mo. OS benefit in the pembro arm was observed across subgroups, including all PD-L1 TPS categories (HR [95% CI] 0.59 [0.38-0.92] for <1%, 0.55 [0.34-0.90] for 1-49%, and 0.42 [0.26-0.68] for ≥50%). ORR was higher with pembro (47.6% vs 18.9%; P < .00001). Grade ≥3 AEs occurred in 67.2% of pts in the pembro arm vs 65.8% in the placebo arm; AEs led to discontinuation of any treatment in 27.7% vs 14.9%, all treatment in 13.8% vs 7.9%, and death in 6.7% vs 5.9%.
 
Conclusions: Pembro + pem + platinum provided superior OS, PFS, and ORR compared with placebo + pem + platinum and had a manageable safety profile in pts with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK alterations. These data suggest first-line pembro + pem and platinum may be a new standard of care for this population.

ORIGINAL ARTICLE NEJM:

Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

L. Gandhi and Others

 

CheckMate -227 Met its Co-primary Endpoint of Progression-free Survival

First-line nivolumab-ipilimumab combo improvedprogression-free survival in patients with advanced non-small cell lung cancerwith high tumor mutational burden 

CHICAGO—Among patients with newly diagnosed advanced non-small cell lung cancer (NSCLC)with high tumor mutational burden (TMB, >10 mutations/Mb), those who received nivolumab (Opdivo) plus ipilimumab (Yervoy) had significantly improved progression-free survival (PFS)compared with patients who received the standard-of-care chemotherapy, according to data from the phase III clinical trial CheckMate -227, presented at the AACR Annual Meeting 2018, April 14-18.

This study is being simultaneously published in The New England Journal of Medicine (see bottom of page).

“Lung cancer is the greatest cause of cancer death world wide and for most patients with newly diagnosed advanced NSCLC, chemotherapy has long been the standard,”said Matthew Hellmann, MD, assistant attending at Memorial Sloan Kettering Cancer Center. “While PD-1 immunotherapies have recently emerged as a critical new treatment option for this patient population, only a minority of all patients with NSCLC respond.”

“This context has yielded two critical opportunities for improvement: to develop effective combinations of therapy that can broaden the population of patients who respond to immunotherapy, and to identify effective biomarkers to predict response,” Hellmann explained.

“The results show that in TMB-high NSCLC patients, nivolumab plus ipilimumab provides improved benefit compared to chemotherapy, increases benefit compared to anti-PD-1 monotherapy, yields durable responses, spares the use of chemotherapy in the first-line setting, and could preserve an effective option in the second lineof therapy, if needed,” Hellmann added.

“These practice-changing data establish the combination of nivolumab plus ipilimumab as a first-line treatment option for patients with high-TMB NSCLC,” Hellmann said. This work also identifies TMB as an important and reliable biomarker that should be tested in patients with newly diagnosed NSCLC, he noted.

CheckMate -227 is a large, open-label, randomized phase III trial of nivolumab, nivolumab plus ipilimumab, or nivolumab plus platinum-doublet chemotherapy (PT-DC) versus PT-DC in patients with stage 4 or recurrent NSCLC who had not received prior treatment. Data from the comparison between the immunotherapy combination and PT-DC are being reported. “The first endpoint presented here examined PFS among patients with high TMB, which is an emerging biomarker that is independent of PD-L1 expression and characterizes about 45 percent of patients with NSCLC, ”Hellmann said.

Of the 299patients with high TMB, 139 received nivolumab plus ipilimumab and160 received chemotherapy. After a minimum follow-up of 11.5 months, patients who received the immunotherapy combination were 42 percent less likely to have their disease progress compared with those who received PT-DC. “PFS at one year was nearly tripled, 43 percent versus 13 percent, as was the duration of response at 1 year, 68 percent and 25 percent,”noted Hellmann. The objective response rate was 45.3 percent in patients who received nivolumab plus ipilimumab, versus 26.9 percent in those who received PT-DC.

Nivolumab plus ipilimumab was well tolerated and the safety profile was similar to the previous experience with this regimen.The rate of treatment-related grade 3-4 toxicities was 31 percent, versus 36 percent with chemotherapy.

“Based on rapidly emerging data suggesting the importance of TMB as a predictive biomarker for benefit with immunotherapy, CheckMate -227 was amended to include — in addition to the initial study design examining nivolumab plus ipilimumab in PD-L1 selected patients — a co-primary endpoint of nivolumab plus ipilimumab versus chemotherapy in patients with high TMB, pre-defined as 10 mutations/Mb,” Hellmann said.

Overall survival data are still maturing and will add further insight into the clinical benefit of nivolumab plus ipilimumab as a first-line option for NSCLC patients with high TMB, Hellmann noted. This study was supported by Bristol Myers Squibb (BMS) and Ono Pharmaceutical. Hellmann is a paid consultant for BMS, Genentech/Roche, AstraZeneca, Merck, Janssen, Novartis, MiratiTherapeutics, and Shattuck labs.

 

ABSTRACT

M. D. Hellmann, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) asfirst-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. 

Background: Nivo + ipi showed promising clinical activity and tolerability as 1L tx for advanced NSCLC in a phase 1 study. Tumor mutation burden (TMB) has emerged as an important biomarker for benefit of immune checkpoint blockade in lung cancer. CheckMate227 (NCT02477826) is a large, open-label, phase 3 study of 1L nivo + ipi, nivo, or nivo + PT-DC vs PT-DC in advanced NSCLC. A preplanned co-primary endpoint was based on TMB to evaluate progression-free survival (PFS) of nivo + ipi vs PT-DC. This is the first phase 3 study to evaluate TMB as a predictive biomarker for immunotherapy as a co-primary endpoint. We report initial results from Part 1 of the study.

Methods: Patients (pts; N=1739) with chemotherapy-naive, histologically confirmed stage IV or recurrent NSCLC, ECOG PS 0−1, and no known sensitizing EGFR/ALK mutations were enrolled in 2 groups: PD-L1 ≥1% or PD-L1 <1%. Pts with ≥1% tumor PD-L1 expression were randomized 1:1:1 to nivo + ipi, nivo, or PT-DC; pts with <1% tumor PD-L1 expression were randomized 1:1:1 to nivo + ipi, nivo + PT-DC, or PT-DC. Tx regimens were nivo 3 mg/kg Q2W + ipi 1 mg/kg Q6W, nivo 240 mg Q2W, or nivo 360 mg Q3W with PT-DC. Pts were treated until disease progression or unacceptable toxicity, up to 2 y. TMB was determined from tumor tissue using the validated Foundation One CDx™ assay (Foundation Medicine, Inc.). Co-primary endpoints were overall survival (OS) for nivo + ipi vs PT-DC in pts with PD-L1-selected tumors and PFS (blinded independent central review) for nivo + ipi vs PT-DC in pts with TMB ≥10 mutations (mut)/Mb.

Results: Baseline characteristics were similar in pts with evaluable TMB and all randomized pts and were balanced between nivo + ipi and PT-DC arms. Minimum follow-up was 11.5 mo. PFS was significantly longer with nivo + ipi vs PT-DC in pts with TMB ≥10 mut/Mb (HR=0.58 [97.5% CI: 0.41, 0.81]; P=0.0002); results were broadly consistent across subgroups, including PD-L1 and histology. The HR for PFS was 1.07 (95% CI: 0.84, 1.35) in pts with TMB <10 mut/Mb. In all randomized pts, the HR for PFS with nivo + ipi vs PT-DC was 0.83 (95% CI: 0.72, 0.96). Objective response rate was 45.3% with nivo + ipi vs 26.9% with PT-DC in pts with TMB ≥10 mut/Mb; median duration of response (95% CI) was not reached (12.2 mo, NR) vs 5.4 (4.2, 6.9) mo, respectively. In treated pts, grade 3-4 treatment-related adverse events rates were 31.3% and 36.1% with nivo + ipi and PT-DC, respectively. Part 1 continues for final OS in the PD-L1-selected co-primary population.

Conclusions: CheckMate 227 met its co-primary endpoint of significantly prolonged PFS with 1L nivo + ipi vs PT-DC in NSCLC with TMB ≥10 mut/Mb regardless of PD-L1 expression. Safety was consistent with previous reports of 1L nivo + ipi for this dose regimen. These results validate the benefit of dual immune checkpoint blockade and the role of TMB as a biomarker to select pts in 1L NSCLC.

 

ORIGINAL ARTICLE NEJM:

Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden

M.D. Hellmann and Others

 

Neoadjuvant Nivolumab was Safe, Yielded Pathologic Responses in Patients With Resectable Lung Cancer

Expansion of circulating tumor-specific T cells after treatment suggested systemic antitumor immunity

CHICAGO — The anti-PD1 immunotherapy nivolumab (Opdivo) given prior to surgical resection of stage 1-3 non-small cell lung cancer (NSCLC) was safe and resulted in major pathological responses in 45 percent of the patients, according to data from a clinical trial presented at the AACR Annual Meeting 2018, April 14-18.

A major pathologicresponse is defined as 10 percent or fewer viable cancer cells detectable in the resected tumor following neoadjuvant treatment.

This study is being simultaneously published in The New England Journal of Medicine (see bottom of page).

“The rationale for neoadjuvant anti-PD1 treatment of resectable NSCLC was essentially to use the primary tumor as a “vaccine” to induce T cells against the tumor antigens that would then circulate through the body systemically and seek out any distant sites of micrometastases,” said senior author of the study Drew Pardoll, MD, PhD, director of Bloomberg~Kimmel Institute for Cancer Immunotherapy and director of Cancer Immunology at Johns Hopkins School of Medicine. “Micrometastases are the primary source of relapse after surgery.

”Conventional neoadjuvant therapy, chiefly comprising chemotherapy or chemoradiotherapy, is given to lung cancer patients to shrink a large, non-metastasized tumor located near an important organ or a blood vessel. The tumor is temporarily shrunk prior to surgery to improve surgical outcomes, Pardoll explained.

“The most stunning finding was that nine of the 20 patients who had surgery after neoadjuvant anti-PD1 had a major pathologic response,” Pardoll noted. “Two patients had no evidence of viable cells in the resected specimen. This is particularly striking given that surgery was done, in most cases, just four weeks after the first dose of anti-PD1 treatment.”

He added, “Our result of a 45 percent major pathologic response rate is very encouraging, considering prior studies showing that a major pathologic response after neoadjuvant chemotherapy in lung cancer is associated with long-term survival.

”Pardoll and colleagues enrolled 21 patients with stage 1-3 ANSCLC in this trial between August 2015 and October 2016; 62 percent had adenocarcinoma. All patients received at least one dose of nivolumab. The median time from second dose of nivolumab to surgery was 18 days, and 20 of 21 eligible patients underwent complete tumor resection.“The anti-PD1 treatment was tolerated well and there were no surgical delays related to neoadjuvant treatment,”Pardoll noted.

Major pathologic responses were observed in the patients’ tumors irrespective of PD-L1 expression by tumor cells. Tumor mutation burden closely predicted the degree of pathologic response. After a median follow-up of 12 months, 16 of 20 patients who underwent surgical resection were alive and recurrence-free. Recurrence-free survival at 18 months was 73 percent, and the median recurrence-free survival had not been reached at the time of data analysis.

To test their hypothesis that checkpoint blockade induces the expansion of tumor-specific T cells in the circulation, the researchers analyzed T-cell responses in the blood on the day of nivolumab treatment and 44 days after surgery. “There was a big burst of tumor-specific T cells in the blood within, in most cases, four weeks after initiation of anti-PD1treatment suggesting that neoadjuvant treatment may have enhanced antitumor immunity systemically,” Pardoll said.

“While it is still too early to tell whether our findings will translate into lower relapse rate and improved survival, pending confirmation in a larger study, we are very optimistic that this approach will eventually be practice-changing and may augment or even replace chemotherapy prior to surgical resection,” Pardoll said.

“We have to be careful not to compare these outcomes with historical outcomes given the small size of this single-arm study; however these initial results are highly encouraging and, allied to the translational science, will spur interest in further neoadjuvant clinical trials across tumor types,” concluded study leader and co-principal investigator of the trial, Patrick Forde, MBBCh, assistant professor of oncology at Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Jamie Chaft, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center is a co-principalinvestigator of the trial.

This study was supported by the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Stand Up To Cancer – Cancer Research Institute Cancer Immunology Translational Research Grant (AACR is the Scientific Partner of SU2C), Bristol-Myers Squibb(BMS) and the International Immuno-Oncology Network, LUNGevity, the International Association for the Study of Lung Cancer & Prevent Cancer, Lung Cancer Foundation of America, the MacMillan Foundation, ECOG-ACRIN, the National Institutes of Health, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Commonwealth Foundation, the Memorial Sloan Kettering Cancer Center Support Grant, and the Johns Hopkins University Cancer Center Support Grant.

Pardoll is an inventor on patents licensed by BMS. Forde has obtained research funding from AstraZeneca, BMS, Novartis, and Kyowa; and is a consultant for AstraZeneca, BMS,Merck, Novartis, Inivata, Abbvie, EMD Serono, and Boehringer Ingelheim.

 

ABSTRACT CT079

P. M. Forde, et al. Neoadjuvant PD-1 blockade in resectable lung cancer

Background: Programmed death-1 (PD-1) blocking antibodies improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, where little progress has been made over the last decade.
 
Methods: Adults with untreated surgically resectable stage I-IIIA NSCLC received two doses of nivolumab (anti-PD-1) preoperatively. The primary endpoints of the study were safety and feasibility. Tumor pathologic response, PD-L1 expression, mutation burden and mutation-associated neoantigen-specific T-cell responses were evaluated.
 
Results: Neoadjuvant nivolumab was had an acceptable side effect profile without surgical delays, and 20 of 21 tumors were completely resected. Major pathologic response occurred in 45% (9/20) of resected tumors. Responses occurred in both PD-L1 positive and negative tumors. Pathologic response significantly correlated with pre-treatment tumor somatic mutation burden. T-cell clones shared between the tumor and peripheral blood increased systemically upon anti-PD-1 treatment in 8 of 9 patients analyzed. Mutation-associated neoantigen-specific T-cell clones, from a primary tumor that underwent pathologic complete response, rapidly expanded in peripheral blood at 2-4 weeks post-treatment, some of these clones were not detected before anti-PD-1.
 
Conclusions: Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced major pathologic responses in 45% of resected tumors. Tumor mutation burden is predictive of pathologic response to anti-PD-1. Anti-PD-1 can induce expansion of mutation-associated neoantigen-specific T-cell clones in peripheral blood.
 

ORIGINAL ARTICLE NEJM:

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

P.M. Forde and Others

 

An Off-the-shelf, Dual-targeted CAR T-cell Product Showed Promising Results in Preclinical Studies

These CAR T cells have the potentialto be mass-produced, stored, and made readily available for cancer patients

CHICAGO — FT819, an off-the-shelf, T-cell receptor (TCR)-less CD19 CAR T-cell product that could potentially be made more accessible to cancer patients than conventional CAR T-cell therapies showed positive results in preclinical specificity, functionality, and efficacy studies, according to data presented at the AACR Annual Meeting 2018, April 14-18.

“Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable results in certain cancer patients. However, the therapy is highly personalized, time-consuming to produce,and consists of only enough cells for a single dose treatment with variable quality,”said Bob Valamehr, PhD, vice president of Cancer Immunotherapy at Fate Therapeutics Inc.“Additionally, today’s CAR T-cell therapies only target a single tumor antigen, which can also limit efficacy.”

“We aimed to overcome these challenges by demonstrating proof-of-concept for an off-the-shelf, dual-targeted CAR T-cell approach. We started with cells from a healthy donor rather than the patient, created a master cell line, and used the master cell line to produce large quantities of ‘universal’CAR19 T cells that are not patient-restricted,” Valamehr explained. “These first-of-kind CAR19 T cells, called FT819, can be packaged, stored, and made readily available for treatment of a large number of patients.”

The master cell line used to manufacture FT819 is an induced pluripotent stem cell (iPSC) line. The use of a master iPSC line for the production of CAR T cells provides distinct advantages over autologous (using cells from a patient’s own body) and allogeneic (using cells from a donor) approaches, Valamehr explained. “A master iPSC line has unlimited capacity to self-renew, and can be banked and renewably used.” Valamehr and colleagues used a proprietary platform that they previously developed to create the master iPSC line.

Conventional CAR T-cell therapies use autologous T cells. New approaches under investigation are using donor T cells; however, donor T cells can attack the patient’s tissues and organs, resulting in a potentially severe and fatal immune system reaction known as graft-versus-host disease (GvHD). In order to avoid GvHD, it is critical to deactivate or remove the TCR, Valamehr explained.

Investigators attempting to engineer billions of donor T cells in bulk have experienced challenges with eliminating the TCR, Valamehr said. “FT819 is TCR-less. We ensure complete elimination of the TCR by directing the CAR to a T-cell receptor α constant (TRAC) locus in a single pluripotent cell,”he noted.

Michel Sadelain, MD, PhD, a collaborator on the FT819 project at Memorial Sloan Kettering Cancer Center, had demonstrated previously that CAR expression under the control of a TRAC locus results in uniform CAR expression, enhances T-cell potency, and vastly outperforms conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukemia.

In addition to a CAR targeting CD19-positive tumor cells, FT819 also has a second targeting receptor designed to broaden the therapy’s efficacy. This CD16 Fc receptor can bind to tumor cells coated with antibodies. This enables FT819 to be administered in combination with other proven cancer treatments, like monoclonal antibodies targeting CD20-positive tumor cells, to potentially overcome tumor antigen escape.

In studies in vitro, FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells by producing cytokines (IFN-gamma, TNF-alpha, and IL2) and mediators of cell death (CD107a/b, perforin, and granzyme B). FT819 was also found to betarget-specific by attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells. Through the expression of CD16 Fc receptor, FT819 was shown to elicit antibody-dependent cell-mediated cytotoxicity when combined with a therapeutic antibody targeting CD20.

“Through the development of FT819, we believe there is significant opportunity to lower the cost of CAR T-cell manufacture; enhance the quality of the product; and create a readily available supply of a more efficacious product to reach more patients in need,” Valamehr said.

FT819 cells were developed using human cells, but the studies used model systems that are not predictive of clinical safety and efficacy, Valamehr cautioned. “We will be required to conduct human clinical trials to fully assess the safety and efficacy of our off-the-shelf iPSC-derived CAR T-cell products.

”FT819 is being developed by Fate TherapeuticsInc., of which Valamehr is a full-time employee.