On June 1, 2019 Nektar Therapeutics (Nasdaq: NKTR) reported that biomarker and clinical data from PIVOT-02 is being presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting in Chicago, Illinois (Press release, Nektar Therapeutics, JUN 1, 2019, View Source [SID1234536786]).

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New baseline biomarker analyses and updated clinical study efficacy and safety results were shared in a presentation titled, "Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab" (Abstract #2623/Poster Board #267) by Michael Hurwitz, Ph.D., M.D. who serves as Assistant Professor of Medicine, Medical Oncology at Yale Cancer Center during the "Developmental Immunotherapy and Tumor Immunobiology" poster session on Saturday, June 1, 2019.

"The Stage IV melanoma patients enrolled in the ongoing PIVOT-02 study continue to experience both deepening and durability of response over time," said Jonathan Zalevsky, Ph.D., Chief Scientific Officer at Nektar Therapeutics. "This translated into a 34% rate of complete response at a 12-month follow-up for the 38 efficacy-evaluable patients in this cohort. Further, 42% of patients achieved a 100% reduction in target lesions. Finally, corresponding lymphocyte data highlight the benefit of replenishing and stimulating T cells continuously over the course of treatment with an I-O doublet regimen."

Bempegaldesleukin (NKTR-214, bempeg) is an investigational, CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 beta-gamma receptor. PIVOT-02 is an ongoing Phase 2 study evaluating bempeg in combination with nivolumab in solid tumors.

Highlights from the biomarker, clinical efficacy and safety data presented at ASCO (Free ASCO Whitepaper) 2019 are provided below:

Biomarkers and Mechanism of Action:

Exploratory biomarker analyses of PIVOT-02 baseline tumor biopsies identified immune signatures that potentially enrich for response in patients with 1L metastatic melanoma and not 1L metastatic urothelial carcinoma.
Notable response rates were seen in both 1L metastatic melanoma and 1L metastatic urothelial cancer patients (ASCO 2019 and ASCO (Free ASCO Whitepaper)-GU 2019), regardless of PD-L1 status or unfavorable tumor microenvironments.
12 Month Follow-Up for 1L Melanoma Cohort in PIVOT-02:
(Response measured by RECIST 1.1 by independent central radiology review for 38 efficacy-evaluable patients per protocol which were treated at the recommended Phase 2 dose in PIVOT-02 and with >1 on treatment scan. Data cut as of March 29, 2019):

At a median time of follow-up of 12.7 months, confirmed objective response rate (ORR) was 53% (20/38) in efficacy-evaluable patients, with 34% (13/38) of patients achieving confirmed complete responses. 42% (16/38) of patients achieved a maximum reduction of 100% in target lesions. DCR, also known as disease control rate (CR+ PR + SD) was 74%.
Median time to response was 2 months. Median duration of response was not reached. At the 12.7 month median follow-up, data were too immature to calculate median progression-free survival (PFS).
80% (16/20) of patients with responses have ongoing responses. Amongst the 35 patients with known pre-treatment PD-L1 status, ORR in PD-L1 negative patients was 6/14 (43%) and in PD-L1 positive patients was 13/21 (62%). One of three patients with unknown PD-L1 baseline status experienced a CR.
The most common (>30%) treatment-related adverse events (TRAEs) were grade 1-2 fatigue (65.9%), pyrexia (61.0%), rash (56.1%), pruritus (48.8%), nausea (41.5%), influenza like illness (39.0%), arthralgia (36.6%), chills (34.1%) and myalgia (31.7%). A total of 6/41 (14.6%) of patients experienced a Grade 3 (G3) or higher TRAE with 4/41 (9.8%) patients discontinuing treatment due to a TRAE. A total of 41 patients have been treated at the RP2D with 3 patients discontinuing prior to 1st scan due to an unrelated treatment-emergent adverse event (n=1) and patient decision (n=2).
A Phase 3 trial evaluating bempeg in combination with nivolumab versus nivolumab in first-line advanced melanoma patients is currently recruiting patients (NCT03635983). A Phase 2 pivotal trial evaluating bempeg in combination with nivolumab in first-line metastatic urothelial cancer is currently recruiting patients (NCT03785925).

Details of the poster presentation are provided below and a link to a copy of the poster presentation is available on Nektar’s corporate website: View Source

Abstract #2623/Poster Board #267
Title: "Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab", Hurwitz, M., et al.
Date: Saturday, June 1, 2019, 8:00 a.m. – 11:00 a.m. Central Time
Location: McCormick Place, Exhibit Hall A

On June 1, 2019 ALX Oncology, a clinical-stage immuno-oncology company developing therapies to block the CD47 myeloid checkpoint mechanism, reported new results from its Phase 1 ALX148 solid tumor program at the 2019 ASCO (Free ASCO Whitepaper) Annual Meeting [Abstract #2514] (Press release, ALX Oncology, JUN 1, 2019, View Source [SID1234536777]). As of April 18, 2019, eighty-two patients with various advanced malignancies were administered ALX148 in combination with standard regimens of either trastuzumab (n=30) or pembrolizumab (n=52). Objective responses were observed in expansion cohorts for both gastric/gastroesophageal junction cancer (G/GEJ) and squamous cell carcinoma of the head and neck (HNSCC). Key results are:

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In response-evaluable patients with HER2 positive G/GEJ (n=18) whose tumors had failed prior HER2-targeted therapy, an overall response rate (ORR) of 22% and a disease control rate (DCR) of 28% were observed.
In patients with HNSCC (n=19) whose tumors had failed prior platinum therapy, an ORR of 16% and a DCR of 26% were observed. In checkpoint naïve subjects (n=10), an ORR of 30% and a DCR of 30% were observed.
ALX148 was well tolerated and the most common treatment-related adverse event in combination with trastuzumab was grade 1/2 fatigue (27%), and with pembrolizumab was grade 1/2 increased AST (15%).
Preliminary data from paired pre- and on-study tumor biopsies from combination cohorts showed a statistically significant increase in intra-tumoral macrophages following ALX148 treatment, consistent with ALX148’s mechanism of action as a myeloid checkpoint inhibitor.
"Emerging anti-tumor activity of ALX148 combined with anti-cancer antibodies supports our hypothesis that blocking CD47 with an Fc-inactive molecule can enhance the anti-cancer immune response in patients with varying solid tumor malignancies," said Sophia Randolph M.D., Ph.D., Chief Medical Officer of ALX Oncology. "With its clinical activity and consistent safety profile, ALX148 may become a new cornerstone of immune therapy. We are excited to continue evaluating its clinical benefit in populations in need of novel treatments."

About ALX148
ALX148, designed for combination therapy, is a fusion protein comprised of an engineered high affinity CD47 binding domain of SIRPα linked to an inactive Fc region of human immunoglobulin. ALX148 potently and specifically binds CD47 and blocks its interaction with SIRPα, thus inhibiting a key immune checkpoint mechanism exploited by cancer cells. In preclinical studies, ALX148 bridges innate and adaptive immunity to maximize anti-tumor response in combinations with targeted anti-cancer antibodies and checkpoint inhibitors via Fc-dependent and Fc-independent mechanisms. No adverse effects on CD47-expressing normal blood cells were seen in ALX148 preclinical studies.

The ALX148 Phase 1 clinical trial is a two-part study that evaluates the safety, pharmacokinetics, and pharmacodynamics of ALX148. Enrollment to the combination therapy portion in which ALX148 is administered with approved anti-cancer antibodies is ongoing. For more information about the Phase 1 study, please visit clinicaltrials.gov, identifier number NCT03013218.

On June 1, 2019 Kite, a Gilead Company (Nasdaq: GILD), reported results from the completed Phase 1 of the ZUMA-3 study evaluating KTE-X19, an investigational CD19 chimeric antigen receptor T (CAR T) cell therapy (Press release, Kite Pharma, JUN 1, 2019, View Source [SID1234536773]). ZUMA-3 is a single-arm Phase 1/2 study in adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL). The results provide guidance on dosing and safety management for KTE-X19 to inform the ongoing Phase 2 study. The data were presented during an oral session at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, May 31 – June 4 (Abstract #7006).

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This press release features multimedia. View the full release here: View Source

By the end of Phase 1, 45 patients received KTE-X19 at one of three different doses levels [2 x 106 cells/kg (n=6), 1 x 106 cells/kg (n=23), or 0.5 x 106 cells/kg (n=16)]. Patients enrolled in this study were primary refractory or relapsed/refractory after at least two prior lines of therapy. Of 41 patients who were evaluable for efficacy after a minimum two months of follow-up (median follow-up of 16 months), 68 percent achieved complete response (CR) or CR with incomplete hematological recovery (CRi) and 100 percent of responders had undetectable minimal residual disease (MRD). Of the 23 patients treated with the dose level that will be used in the ongoing Phase 2 study (1 x 106 cells/kg), 19 were evaluable for efficacy. At the time of data cut-off (median duration of remission = 12.9 months), 16 (84 percent) patients achieved CR or CRi, and 12 patients (75 percent) were in ongoing response.

No dose-limiting toxicities (DLTs) were identified. Grade ≥3 cytokine release syndrome (CRS) events and neurologic events occurred in 29 percent and 38 percent of all patients, respectively. As previously reported, two patients experienced KTE-X19–related Grade 5 adverse events (AEs) during the study; one developed stroke in the context of CRS and neurologic events, and one experienced multiorgan failure secondary to CRS. Among patients receiving 1 x 106 cell/kg (n=23), 26 percent experienced Grade ≥3 CRS, and 43 percent experienced Grade ≥3 neurologic events.

A revised AE management protocol was implemented in nine patients treated with 1 x106 cells/kg of KTE-X19 during the study. In this revised protocol, corticosteroids were initiated at onset of Grade ≥2 neurologic events (versus previous onset of Grade 3) and tocilizumab was only given for management of toxicities in the context of CRS (versus prophylactic administration in Cohort 2). Of those patients, two (22 percent) had Grade 3 CRS and one (11 percent) had Grade 3 neurologic events. There were no Grade 4/5 events.

"Adults with relapsed or refractory ALL represent an extremely difficult-to-treat patient population," said Bijal Shah, MD, ZUMA-3 investigator and medical oncologist, Moffitt Cancer Center, Tampa, Florida. "We’re encouraged by the high response rates in this study, as well as the reduced incidence and severity of CRS and neurologic events that were observed following implementation of the revised safety management protocol. We are now evaluating the use of KTE-X19 at the selected dose with this safety management protocol in the ongoing ZUMA-3 Phase 2 study."

"The completion of the Phase 1 portion of the ZUMA-3 trial is an important milestone for our second investigational CAR T cell therapy," said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead. "We are pleased with the high response rates observed with KTE-X19 in this trial, and the progress of our broader effort aimed to further improve the benefit/risk profile of CAR T therapy through the investigation of novel safety management approaches."

This abstract has also been selected to be included in the 2019 Best of ASCO (Free ASCO Whitepaper) program, which will be held this summer following the ASCO (Free ASCO Whitepaper) Annual Meeting.

KTE-X19 is an investigational therapy that has not been approved by the U.S. Food and Drug Administration (FDA) or any regulatory authority for any uses. Efficacy and safety have not been established.

About ALL

ALL is an aggressive type of blood cancer which can also involve the lymph nodes, spleen, liver, central nervous system and other organs.

About ZUMA-3

ZUMA-3 is an ongoing multicenter, registrational Phase 1/2 study in adult patients (≥18 years old) with ALL whose disease is refractory to or has relapsed following standard chemotherapy or hematopoietic stem cell transplantation. The objectives of the study are to evaluate the safety and efficacy of KTE-X19 in this patient population.

About KTE-X19

KTE-X19 is an investigational CD19 CAR T cell therapy. KTE-X19 has the same construct as axicabtagene ciloleucel; however, the manufacturing process for KTE-X19 differs from that of axicabtagene ciloleucel and includes the enrichment of lymphocytes. Lymphocyte enrichment is necessary in certain B-cell malignancies for which KTE-X19 in under investigation. KTE-X19 is currently in Phase 1/2 trials in acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).

On June 1, 2019 The results of PharmaMar’s (MSE: PHM) Phase II study with lurbinectedin as a single agent for the treatment of relapsed small cell lung cancer were presented to the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) conference, which is currently being held in Chicago. The results of this trial, which achieved its primary endpoint, have been presented orally by Dr. Luis Paz-Ares, Head of the Oncology Department at the Hospital Universitario 12 de Octubre in Madrid and lead author of the study.

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In his presentation entitled "Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial", Dr.Paz-Ares updated the data from the lurbinectedin study, where an ORR of 35.2% in the total population, 45% in patients with sensitive disease (CTFI≥90 days, i.e., those who have suffered a relapse of the disease in a period greater than or equal to 90 days) and 22.2% in patients with resistant disease (CTFI<90 days, i.e., those patients who have suffered a relapse of the disease in a period less than 90 days) has been seen.

"Lurbinectedin is showing to be a new potential treatment alternative for second-line small cell lung cancer, where, until now, no progress has been made for more than two decades," says Dr. Luis Paz-Ares.

Additional Study Results

The Disease Control Rate (DCR) was 68.6% in the overall population, 81.7% in sensitive patients and 51.1% in resistant patients.
The median Duration of Response (DOR) was 5.3 months in the overall population, 6.2 months in sensitive patients and 4.7 months in resistant patients.
The median Progression Free Survival (PFS) was 3.9 months in the overall population, 4.6 months in sensitive patients, and 2.6 months in resistant patients.
The median OS was 9.3 months in the overall population, 11.9 months in sensitive patients, and 5.0 months in resistant patients.
"Having been chosen to present positive results at ASCO (Free ASCO Whitepaper) is an honor for any pharmaceutical company. These results demonstrate that lurbinectedin is a strong candidate to become a therapeutic alternative for patients with small cell lung cancer, a large unmet medical need," explains José María Fernández, President of PharmaMar.

In terms of product safety, lurbinectedin has shown a favorable and manageable safety profile. The most common treatment-related adverse effects have been neutropenia, nausea or vomiting, and fatigue.

Grade 3-4 neutropenia occurred in 22.9% of cases, grade 3-4 febrile neutropenia in only 4.8%, grade 3-4 anemia in 6.7%, and grade 3-4 thrombocytopenia in 4.8%.

By way of reference, the data provided for lurbinectedin compares favorably (non head-to-head) to the data included in the topotecan FDA label1, the last molecule approved for second-line treatment, in 1996. The topotecan arm saw an ORR of 24%, [median] PFS of 3.9 months and median OS of 5.8 months was seen. In terms of safety, topotecan showed grade 4 neutropenia in 70% of the patients, grade 3-4 febrile neutropenia in 28% and grade 3-4 anemia in 42%. The difference between the results of both these molecules, although not having comparable face-to-face studies, speaks of the potential of lurbinectedin as a potential new alternative treatment for second-line small cell lung cancer.

The single-agent lurbinectedin study is a single-arm, Phase II, multicenter trial, involving 105 patients recruited from 39 centers in 9 countries in Western Europe along with the USA, studying the safety and efficacy of lurbinectedin in second line treatment of small cell lung cancer.

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On June 1, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported results from the CDX-3379 clinical program at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Celldex Therapeutics, JUN 1, 2019, View Source [SID1234536771]). To date, three studies of CDX-3379 have enrolled patients with head and neck squamous cell carcinoma (HNSCC), including the ongoing Phase 2 exploratory study of CDX-3379 in combination with Erbitux (cetuximab) in patients with cetuximab-resistant, advanced human papillomavirus (HPV) negative HNSCC who have previously been treated with an anti-PD1 checkpoint inhibitor.

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Emerging data from the Phase 2 study and earlier studies of CDX-3379 suggest that antitumor activity may be associated with somatic mutations in certain genes. Based on these observations, Celldex conducted an exploratory biomarker analysis in 18 HNSCC patients across the CDX-3379 clinical development program. These results support the further development of CDX-3379 in biomarker-selected patient populations and were highlighted during a presentation at ASCO (Free ASCO Whitepaper) by Julie E. Bauman, MD, MPH, Professor of Medicine, Chief, Division of Hematology and Oncology, Associate Director, Translational Research, University of Arizona Cancer Center, lead author for the poster and an investigator in the Phase 2 study.

"We have observed intriguing clinical activity across a number of patients with similar gene mutation patterns in a disease that has extremely limited treatment options and a particularly poor prognosis," said Dr. Bauman. "While the data are early, they are provocative and suggest the potential for a biomarker enrichment strategy that could change the standard of care for these patients. I look forward to the opportunity to obtain additional data on CDX-3379 in biomarker selected patient populations."

CDX-3379 is a human monoclonal antibody that uniquely blocks the activity of ErbB3 (HER3). ErbB3 is expressed in many cancers, including head and neck squamous cell cancer (HNSCC) and is believed to be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies.

Biomarker analysis

Next-generation sequencing was performed on tumor samples from 18 patients with HNSCC treated with CDX-3379 across the three clinical studies. This data set included four patients with clinical responses, including two durable complete responses (11+ months and 8.3 months), an exceptional partial response (greater than 92% tumor shrinkage) and an unconfirmed partial response; eight patients with stable disease and/or tumor shrinkage; and, six patients with progressive disease.

Across the CDX-3379 program, FAT1 and NOTCH1, NOTCH2, or NOTCH3 mutations and primary tumor site of oral cavity were associated with clinical activity (clinical response, tumor shrinkage and stable disease) in HNSCC
All four clinical responses occurred in patients with FAT1 mutations
All four clinical responses occurred in patients with a primary tumor site of oral cavity
Three of the four clinical responses occurred in patients who also had NOTCH1, NOTCH2 or NOTCH3 mutations
Also, of note, all patients (n=7 of 18) who experienced clinical benefit (objective response or stable disease greater than or equal to 12 weeks) had FAT1 and/or NOTCH1-3 mutations.
Current literature suggests that loss of FAT1 function results in activation of the transcriptional cofactor YAP11; YAP1 has been shown to upregulate components of ErbB signaling pathways2,3, including the ErbB3 ligand NRG14
Inactivating mutations in the FAT1 and NOTCH genes have been identified in 32% and 26% of HPV(-) HNSCC tumors, respectively5
Preclinical studies investigating the association of CDX-3379 sensitivity and inactivating mutations of FAT1 and other genes are ongoing

Phase 2 CDX-3379 Study Results and Next Steps

This multicenter, open-label, Phase 2 study of CDX-3379 in combination with cetuximab is designed to enroll approximately 30 patients with cetuximab-resistant, advanced, HPV negative HNSCC who have previously been treated with an anti-PD1 checkpoint inhibitor, a population with limited options and a particularly poor prognosis. Cetuximab is dosed weekly (initial dose at 400 mg/m2 IV, then 250 mg/m2 IV); CDX-3379 (12 mg/kg IV) is administered once every three weeks. Treatment continues until disease progression or intolerance, and assessments occur every six weeks. Using a Simon two-stage design, the first stage of study was designed to enroll 13 patients, and if at least one patient achieved a partial response or complete response, enrollment could progress to the second stage; this objective was met.

Fifteen patients were enrolled in stage 1 of the study. Patients had a median of 3 (range of 2-6) prior cancer therapy treatments. All patients had received prior checkpoint inhibitor treatment and 14 of 15 patients were cetuximab refractory. Notable clinical activity was observed in this refractory patient population where treatment options are limited.

A durable confirmed complete response (11+ months) was observed; this response remains ongoing and the patient continues to receive treatment.
An unconfirmed partial response (uPR) in a patient that had not received cetuximab was also observed.
7 patients experienced stable disease (47%; includes uPR).
A clinical benefit rate of 29% was achieved (objective response or stable disease greater than or equal to 12 weeks).
Dose reductions and/or delays to the combination therapy in the majority of patients may have impacted the magnitude of anti-tumor activity; dose modifications are being considered for future studies.
CDX-3379 in combination with cetuximab was generally associated with the expected target-mediated adverse events of diarrhea and rash.
Celldex intends to incorporate evaluation of biomarkers for patient selection into the CDX-3379 development program, either through amending the existing study or concluding the study and initiating a new clinical trial. The Company, working together with investigators and key opinion leaders in the treatment of HNSCC, anticipates finalizing these plans in the coming weeks.

Erbitux is a registered trademark of Eli Lilly & Co.
1Martin D, Nat Commun 2018. 2Zhang J, Nat Cell Biol 2009. 3Wang C, Cancer Res 2017. 4He C, Oncogene 2015. 5Cancer Genome Atlas Network, Nature 2015.

About CDX-3379
CDX-3379 is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively binds and inhibits ErbB3 activity. ErbB3 may be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies, and it is expressed in many cancers, including head and neck, thyroid, breast, lung and gastric cancers, as well as melanoma. The proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. CDX-3379 also has potential to enhance anti-tumor activity and/or overcome resistance in combination with other targeted and cytotoxic therapies to directly kill tumor cells.