On December 11, 2017 Syntimmune presented Poster Presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting, Atlanta, Georgia (Press release, Syntimmune, DEC 11, 2017, View Source [SID1234522534]).

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On December 11, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the presentation of six posters highlighting preclinical and clinical data sets for TGR-1202 (umbralisib), the Company’s once-daily PI3K delta inhibitor, and TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting, currently being held at the Georgia World Congress Center in Atlanta, Georgia (Press release, TG Therapeutics, DEC 11, 2017, View Source [SID1234522557]).

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated, "We are very pleased by the data presented yesterday and today during the ASH (Free ASH Whitepaper) annual meeting. The preclinical data help us to better understand the difference between TGR-1202 and other agents in the class and offers a more complete rationale for the differentiated safety profile seen in the clinic. With the updated and expanded integrated safety analysis of TGR-1202 alone and in combination with other agents, we believe we have provided the long-term follow-up sufficient to allay any lingering safety concerns related to TGR-1202 caused by the toxicity profile of first generation PI3K delta inhibitors." Mr. Weiss continued, "In 2018, with registration-directed data expected in CLL and NHL, our focus will turn to showcasing the efficacy of TGR-1202 and our proprietary combination of TG-1101 plus TGR-1202, our U2 combination, ideally leading to NDA/BLA filings in CLL and NHL."

The following summarizes the highlights from each poster presented at the ASH (Free ASH Whitepaper) 2017 meeting.

Clinical Data Presentations:

An Integrated Safety Analysis of the Next Generation PI3K Delta Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

This presentation includes data that were pooled from 5 completed or ongoing Phase 1 or 2 studies containing TGR-1202, including a total of 347 patients with relapsed or refractory hematologic malignancies. Patients were heavily pretreated, with 50% of patients having seen 3 or more prior lines of therapy.

Highlights from this poster include:

● 347 patients have been treated with TGR-1202 across the 5 studies in this pooled analysis, with median duration of exposure of 6.5 months, and 176 patients on drug for 6+ months, 104 patients for 12+ months, with the longest patients on daily TGR-1202 for 4+ years
● In longer follow-up and in an expanded patient population, TGR-1202 exhibits a differentiated safety profile compared to prior generation PI3K delta inhibitors
● Discontinuations due to adverse events (AEs) were rare at under 10% for all studies
● Grade 3/4 AEs commonly associated with PI3K delta inhibitors have been rare, with pneumonitis (< 0.5%), transaminitis (~2%) and colitis (< 1%), the latter occurring with no apparent association to time on therapy
● Improved tolerability with few discontinuations due to AEs has allowed patients to remain on continuous dosing to achieve and sustain promisingly high rates of response:
o 85% Overall Response Rate (ORR) for single agent TGR-1202 in relapsed/refractory Chronic Lymphocytic Leukemia (CLL)
o 53% ORR for single agent TGR-1202 in relapsed/refractory Follicular Lymphoma (FL)

KI Intolerance Study: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) In Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-delta Inhibitor Therapy (Abstract Number 4314)

This poster presentation includes data from patients with CLL who are intolerant to prior BTK or PI3K delta inhibitor therapy who were then treated with single agent TGR-1202. To be eligible for the study patients had to have received prior treatment with a BTK inhibitor (ibrutinib, acalabrutinib) or a PI3K delta inhibitor (idelalisib, duvelisib) and discontinued therapy due to intolerance within 12 months of starting treatment on this study. Thirty-three patients were evaluable for safety (30 patients with ibrutinib intolerance, and 3 patients with idelalisib intolerance) of which 32 were evaluable for efficacy (1 patient had a confirmed Richter’s Transformation (RT) at enrollment which did not meet eligibility criteria). TGR-1202 appears to demonstrate a favorable safety profile in patients intolerant to prior ibrutinib or idelalisib, with only 2 patients (6%) discontinuing due to an adverse event, neither of which was a recurrent AE from prior TKI therapy.

Highlights from this poster include:

● 94% (30 of 32) of patients remain progression-free
● Median time on study at the data cut off was approximately 6 months with the majority of patients continuing on study and follow-up ongoing
● No patient discontinued TGR-1202 due to a recurrent AE which led to discontinuation from their prior kinase inhibitor

Phase I/II Study of Pembrolizumab in Combination with Ublituximab (TG-1101) and Umbralisib (TGR-1202) in Patients with Relapsed/Refractory CLL (Abstract Number 3010)

This presentation includes data from patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Richter’s Transformation (RT) treated with the triple combination of TG-1101, TGR-1202, and pembrolizumab. Eleven patients were evaluable for safety (9 CLL patients and 2 RT patients) and 10 were evaluable for efficacy (9 CLL and 1 RT), with one patient too early to evaluate.

Highlights from this poster include:

● One AE of increased LFTs was observed which met criteria for DLT; patient was re-challenged and remains on study treatment with TGR-1202 maintenance now 15+ months
● 78% (7 of 9) ORR in patients with relapsed/refractory CLL
● 75% (3 of 4) ORR in BTK refractory CLL patients
● Responses have been durable with the first patient progression-free for 24+ months

Preclinical Data Presentations:

Differential Regulation of T Cells By PI3K Delta Inhibitors in a CLL Murine Model (Abstract Number: 3009)

This poster presentation included preclinical data describing the differential regulation of human T cells by TGR-1202 in a preclinical CLL murine model.

Highlights from this poster include:

● TGR-1202 oral treatment induced less incidence of toxicity in CLL mice compared to other PI3K delta inhibitors
● TGR-1202 relatively preserved Treg quantity and function in a dose dependent manner compared to other PI3K delta inhibitors in normal and murine CLL T cells
● Inhibition of casein-kinase 1 epsilon (CK1e) by TGR-1202 may explain the relative preservation of Treg cells in these in-vivo models

Umbralisib/TGR-1202 As a Novel Dual PI3K/CK1 Inhibitor Has a Unique Therapeutic Role in Silencing Oncogenes in Aggressive Lymphomas (Abstract Number 2809)

This poster presentation expanded on existing preclinical data demonstrating that TGR-1202 is synergistic with carfilzomib in certain aggressive lymphoma cell lines.

Highlights from this poster include:

● TGR-1202 is highly synergistic with the proteasome inhibitor carfilzomib in cell line models of double hit lymphoma and mantle cell lymphoma
● Based on this preclinical work, a Phase 1 clinical study to evaluate the safety and efficacy of TGR-1202 in combination with carfilzomib is currently enrolling patients

PI3K Delta Inhibitors Induce Primary Monocyte Cytotoxicity but Do Not Alter Monocyte Differentiation (Abstract Number 4284)

This poster presentation included preclinical data exploring the effect of PI3K delta inhibitors on monocyte activity.

Highlights from this poster include:

● The clinical benefit and initial lymphocytosis seen with PI3K delta inhibitors in CLL may be related in part to direct effects on monocyte derived cells
● Idelalisib and TGR-1202 differed in the extent of monocyte cytotoxicity induced and inhibition of pAKT
● The direct effects of PI3K delta inhibitors on monocytes suggests these drugs may have efficacy beyond B-cell malignancies, including in monocytic neoplasms or other malignancies with monocyte derived cells in the tumor microenvironment

The above referenced presentations, are available on the Publications page of the Company’s website at www.tgtherapeutics.com.

On December 11, 2017 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, and Celgene Corporation (NASDAQ: CELG) reported additional data from the TRANSCEND study of JCAR017 (lisocabtagene maraleucel; liso-cel) in patients with relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (NHL) in a presentation at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Celgene, DEC 11, 2017, View Source [SID1234522552]).

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"We are highly encouraged by the latest efficacy and tolerability data, particularly at dose level two, as these are patients with a poor prognosis who need better treatment options," said Sunil Agarwal, M.D., Juno’s President of Research and Development. "These data support a potential best-in-class profile and further support the importance of a defined cell product. We continue to enroll our pivotal cohort in DLBCL patients and over the next twelve to eighteen months we intend to explore earlier lines of therapy, additional therapeutic areas, and combinations."

TRANSCEND is an open-label, multicenter Phase 1 study to determine the safety, pharmacokinetics, and antitumor activity of JCAR017 in adult patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.

The data were based on a cutoff date of October 9, 2017 and presented by Jeremy Abramson, M.D., of Massachusetts General Hospital, who is a Principal Investigator for the TRANSCEND study. They add to those disclosed on November 1, 2017 in ASH (Free ASH Whitepaper) Abstract #581.

As with previous readouts, the TRANSCEND data were presented for both the core and full groups. The core group (N=67) includes 29 patients who received dose level two (DL2 = 100 million cells), 34 patients who received dose level one (DL1 = 50 million cells), and 4 patients who received dose level one twice, approximately 14 days apart.

The core group includes patients with DLBCL (NOS and transformed from follicular lymphoma) who are ECOG Performance Status 0-1. These patients represent a high-risk patient population, with approximately 90% of treated patients having one or more predictors of poor survival, including double or triple hit lymphoma, being chemorefractory to front-line or subsequent therapies, never reaching a complete remission with prior treatments, or never having undergone an autologous transplant. Enrollment of the pivotal cohort is ongoing with the core group at DL2.

The full analysis group represents evaluable r/r patients in the DLBCL cohort (N=91), which includes an additional 24 patients with poor performance status (ECOG Performance Status 2) or with niche subtypes of aggressive NHL. In both analysis groups all efficacy data are based on at least one month of follow-up with a 28-day restaging scan and all safety evaluable data are based on having received JCAR017 (liso-cel) with at least one month of follow-up. Product was available for 98% (126/128) of patients apheresed in the DLBCL cohort.

"The results of this study continue to show the exciting potential of this CAR T therapy," said Jay Backstrom, Chief Medical Officer and Global Head of Regulatory Affairs for Celgene. "Our collaboration with Juno reflects our commitment to delivering transformational treatments to patients with blood cancers such as non-Hodgkin lymphoma."

Topline data from the presentation as of the October 9, 2017 data cutoff date included:

Responses in core group

At DL2, the data showed a 3 month overall response rate (ORR) of 74% (14/19) and a 3 month complete response (CR) rate of 68% (13/19). Of patients that have reached 6 months of follow-up, 50% (7/14) were in CR. Across doses, 80% (16/20) of patients with CR at 3 months stayed in CR at 6 months, and 92% (11/12) of patients in response at 6 months remain in response as of data cutoff.
Across doses, median duration of response (DOR) was 9.2 months and median durability of CR was not reached.
Tolerability in core group

1% (1/67) experienced severe cytokine release syndrome and 15% (10/67) experienced severe neurotoxicity.
36% (24/67) had any grade CRS and 21% (14/67) had any grade NT.
58% (39/67) had no CRS or NT of any grade.
At dose level 1, 3% (1/34) experienced severe CRS and 21% (7/34) experienced severe NT.
At dose level 2, 0% (0/29) experienced severe CRS and 7% (2/29) experienced severe NT.
13% (9/67) received tocilizumab and 18% (12/67) received corticosteroids.
Tolerability across doses in full group

1% (1/91) experienced severe CRS and 12% (11/91) experienced severe NT.
35% (32/91) had any grade CRS and 19% (17/91) had any grade NT.
60% (55/91) had no CRS or NT of any grade.
The most common treatment-emergent adverse events (TEAEs) other than CRS and NT that occurred at ≥25% included neutropenia (49%), anemia (38%), fatigue (37%), thrombocytopenia (29%), nausea (27%), and diarrhea (25%). The most common TEAEs were similar between core and full groups.
JCAR017 (liso-cel) is a defined composition CD19-directed CAR T cell product candidate using a 4-1BB costimulatory domain. Juno believes JCAR017’s clinical profile could enable outpatient administration. A biologics license application filing is expected to be completed in the second half of 2018, with approval as early as the end of 2018.

ASH Investor and Analyst Event and Webcast

The Juno ASH (Free ASH Whitepaper) Investor and Analyst Event and webcast will be held Monday, December 11, 2017 at 8:30 p.m. Eastern Time. The webcast can be accessed live on the Investor Relations page of Juno’s website, www.JunoTherapeutics.com, and will be available for replay for 30 days following the event.

On December 11, 2017 Reata Pharmaceuticals, Inc. (Nasdaq:RETA) ("Reata" or "the Company"), a clinical-stage biopharmaceutical company, reported the presentation of interim data from the ongoing Phase 1b portion of the REVEAL study of omaveloxolone in combination with approved checkpoint inhibitor (CI) therapies, ipilimumab or nivolumab, for the treatment of Stage III or IV unresectable or metastatic melanoma (Press release, Reata Pharmaceuticals, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322028 [SID1234522532]). The data were presented in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno Oncology Congress 2017 in Geneva, Switzerland by lead author Dr. Sapna Patel, Assistant Professor, Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center.

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All enrolled patients were required to have biopsy positive inducible nitric oxide synthase (iNOS), which is an independent predictor of poor survival in melanoma patients. Emerging translational data suggest that iNOS is a key mediator of myeloid-derived suppressor cells (MDSCs), whose presence has been shown to correlate with reduced activity of CIs. Of the 30 patients enrolled in REVEAL with evaluable tumor restaging, 7/30 (23%) of patients were checkpoint inhibitor-naïve, while 23/30 (77%) of patients were refractory to prior checkpoint inhibitor therapy. The overall response rate (confirmed + unconfirmed) observed in all evaluable patients was 8/30 (27%, 6 partial responses (PR) and 2 complete responses (CR)).

In CI-naïve patients, 4/7 (57%) had objective responses including 1 CR. 3/18 (17%) patients treated with omaveloxolone + nivolumab who were refractory to prior checkpoint inhibitor therapies had objective responses, including 1 CR. The majority of responses have been durable and are ongoing. Omaveloxolone treatment was associated with decreases in tumor iNOS, programmed death ligand 1 (PD-L1), and indoleamine 2,3-dioxygenase (IDO-1) expression. No serious AEs considered related to omaveloxolone have been reported to date. Commonly reported treatment-related adverse events included fatigue, nausea, pruritus, transaminase increases, and decreased appetite.

"The ongoing REVEAL trial data suggests that omaveloxolone may have activity in patients who are refractory to checkpoint inhibitors, which is an emerging and large unmet need," said Colin Meyer, M.D., Chief Medical Officer of Reata. "We are continuing with the dose escalation phase of the study to identify the optimal dose, and upon completion, we will determine the next steps in the clinical development program for omaveloxolone in melanoma."

On December 11, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the Phase III IMmotion151 study met its co-primary endpoint of investigator-assessed progression-free survival (PFS) and demonstrated that the combination of Tecentriq (atezolizumab) and Avastin (bevacizumab) provided a statistically significant and clinically meaningful reduction in the risk of disease worsening or death (PFS) in people whose disease expressed the PD-L1 (programmed death-ligand 1: Expression ≥1%) protein compared with sunitinib for the first-line treatment of people who have advanced or metastatic renal cell carcinoma (mRCC) (Press release, Hoffmann-La Roche, DEC 11, 2017, View Source [SID1234522504]).

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Observations of a pre-specified subgroup analysis of the Tecentriq and Avastin combination indicated that, in people whose disease expressed PD-L1, a numerical difference favouring Tecentriq was seen across all patient risk factor groups (favourable, intermed­iate and poor) compared to sunitinib; however, due to the study design these data could not be assessed for statistical significance and are descriptive only. Assessment of secondary endpoints is ongoing. Safety for the Tecentriq and Avastin combination appeared consistent with the known safety profile of the individual medicines and what was previously reported in the Phase II IMmotion150 study. No new safety signals were identified with the combination.

Results will be presented at an upcoming oncology conference in 2018. Top-line results from the co-primary endpoint of overall survival (OS) are not mature.

"We are encouraged by these results as they add to the emerging body of evidence that supports our rationale for this combination. We believe that the regimen of Tecentriq and Avastin may enhance the potential of the immune system in the initial treatment of advanced kidney cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We will discuss these data with health authorities globally and hope to bring this combination forward as a potential new treatment option to patients as soon as possible.’’
IMmotion151 is the second successive positive Phase III study of Tecentriq that includes an Avastin combination component as an initial treatment. This follows the positive Phase III non-squamous non-small cell lung cancer (NSCLC) IMpower150 study that showed Tecentriq and Avastin plus chemotherapy demonstrated a PFS advantage over Avastin plus chemotherapy.

About the IMmotion151 study
IMmotion151 is a Phase III multicentre, randomised, open-label study to evaluate the efficacy and safety of Tecentriq and Avastin versus sunitinib in people with inoperable, locally advanced or metastatic renal cell carcinoma (RCC) who have not received prior systemic active or experimental therapy. It enrolled 915 people globally who were randomised 1:1 to receive Tecentriq and Avastin, or sunitinib alone.

People in the Tecentriq and Avastin arm received Tecentriq at a fixed dose of 1200 milligrams (mg) and Avastin at a dose of 15 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until loss of clinical benefit or unacceptable toxicity. People in the sunitinib arm received sunitinib 50 mg orally, once daily for 4 weeks followed by 2 weeks rest until loss of clinical benefit or unacceptable toxicity.

The co-primary endpoints were PFS, as determined by the investigator using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in people whose tumours expressed PD-L1 [PD-L1 expression ≥1 percent on immune cells (IC)], and OS in the overall study population (intention-to-treat, ITT). PD-L1 expression was prospectively assessed using an immunohistochemistry (IHC) test (SP142) developed by Roche Tissue Diagnostics.
Stratification factors included the presence or absence of liver metastases; level of IC staining for PD-L1 (≥1 percent vs. <1 percent) and Memorial Sloan-Kettering Cancer Center (Motzer) risk score. The Motzer prognostic scoring system predicts for OS based upon an individual’s baseline clinical and laboratory characteristics.
Depending on the presence of one or several of five variables (risk factors), patients are classified in one of the three risk groups: ‘Favourable’ with 0 risk factors, ‘Intermediate’ with 1–2 risk factors and ‘Poor’ with ≥ 3 risk factors.

About RCC
Kidney cancer remains one of the most common cancers in the world, accounting for over 140,000 deaths worldwide each year,1 with renal cell carcinoma (RCC) accounting for approximately 90% of all cases.2 Over 300,000 people are diagnosed with RCC every year and currently only about 1 in 10 people are alive beyond 5 years following diagnosis of metastatic disease.

RCC occurs when abnormal cells develop in the tissue of the kidneys, specifically in the small tubes (also known as tubules) where our blood is filtered.4 Typically, RCC is a single tumour in one kidney but, in rare cases, there can be multiple tumours, which can occur in one or both kidneys.

Despite recent progress in the field of kidney cancer, treatment options for people with the disease remains limited.

About Tecentriq (atezolizumab)
Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Tecentriq is already approved in the European Union, United States and more than 50 countries for people with previously treated metastatic NSCLC and for people with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About Avastin (bevacizumab) in RCC
Avastin (bevacizumab) is an anti-VEGF inhibitor. VEGF (vascular endothelial growth factor) is a protein that stimulates the formation and maintenance of blood vessels and has been shown to play a key role in the development of RCC.
RCC tumours are highly vascularised, meaning they have many blood vessels and also exhibit a high concentration of VEGF5. There is, therefore a strong rationale for medicines such as Avastin that block the VEGF pathway. Avastin is the only currently available treatment for patients with mRCC that directly inhibits VEGF.

There is a strong scientific rationale to support further investigation of Tecentriq and Avastin in combination. The Tecentriq and Avastin regimen may enhance the potential of the immune system to combat first-line advanced NSCLC and mRCC. Avastin, in addition to its established anti-angiogenic effects, may further enhance Tecentriq’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumour infiltration and enabling priming and activation of T-cell responses against tumour antigens.

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.
To learn more about the Roche approach to cancer immunotherapy please follow this link:
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