On November 11, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported an oral presentation with updated data on its study of NY‑ESO SPEAR (Specific Peptide Enhanced Affinity Receptor) T‑cells in the ongoing synovial sarcoma trial at the 2016 Connective Tissue Oncology Society (CTOS) annual meeting presented by Dr. Sandra P. D’Angelo of the Memorial Sloan Kettering Cancer Center (Press release, Adaptimmune, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221814 [SID1234516498]). This presentation included an update to Cohort 1 median survival data. The meeting is being held at the Corinthia Hotel in Lisbon, Portugal from November 9 through 12, 2016.

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In an oral presentation entitled, "Open Label Non-Randomized Multi-Cohort Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO SPEAR T-cells in HLA-A*02+ Patients with Synovial Sarcoma," Dr. Sandra P. D’Angelo of the Memorial Sloan Kettering Cancer Center described that median survival for Cohort 1 is now calculated to be ~18 months (80 weeks), compared to ~13 months (56 weeks) as previously reported. The updated median survival calculation is based on analyses of additional patient follow-up data (cutoff of September 30, 2016). Other updates indicate that there continue to be additional partial responses among low NY-ESO expressors in Cohort 2, which is ongoing.

On November 11, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported the presentation of data at the 2016 Society for Immunotherapy for Cancer (SITC) (Free SITC Whitepaper) annual meeting (Press release, Adaptimmune, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221778 [SID1234516497]). The posters summarize: (1) preclinical data from Adaptimmune’s wholly-owned MAGE-A4 SPEAR (Specific Peptide Enhanced Affinity Receptor) T‑cells; (2) preclinical data from the Company’s second generation SPEAR T-cell, which is engineered to overcome immunosuppression in the tumor microenvironment by blocking the effects of transforming growth factor Beta (TGF-Beta); and (3) a single-patient case study from the Company’s ongoing synovial sarcoma study. The 2016 SITC (Free SITC Whitepaper) annual meeting is being held at the Gaylord National Hotel & Convention Center in National Harbor, Maryland on November 9 through 13, 2016.

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"We are pleased to present the preclinical data that underpins the decision to progress our next SPEAR T‑cell candidate, MAGE-A4, into clinical trials and we plan to file an IND in early 2017," said Gwendolyn Binder-Scholl, PhD Adaptimmune’s Chief Technology Officer. "MAGE–A4 is an attractive target which is broadly expressed in multiple solid tumors. Our MAGE-A4 SPEAR T-cell candidate has shown promising activity without any major safety concerns identified by our extensive preclinical testing. In addition, we are presenting initial data from a second generation NY-ESO SPEAR T-cell to overcome TGF‑Beta immunosuppression in the tumor microenvironment, as well as translational results from a case study of a patient with synovial sarcoma treated with NY-ESO SPEAR T‑cells. We believe that this type of data underscores our leadership in the field, and helps us to improve the function of SPEAR T-cells and inform future clinical study design."

Preclinical Testing of Wholly-owned MAGE-A4 SPEAR T-cells
In a poster presentation entitled, "Preclinical evaluation of an optimal-affinity MAGE-A4 T-cell receptor for adoptive T-cell therapy," Daniel Williams, Ph.D. of Adaptimmune, presented data examining MAGE-A4 expression in tumor and non-tumor tissues, and generation of an optimal affinity-enhanced MAGE-A4 SPEAR T‑cell.

MAGE-A4 is a cancer‑testis antigen, one of a number of genes with expression in adult tissues restricted to the testes, but also known to be expressed in several tumor types;
Target validation data indicates that MAGE-A4 is a very attractive target due to widespread and frequent expression in multiple tumor types including non‑small cell lung cancer, bladder, melanoma, head and neck, ovarian, esophageal, and gastric cancers with no detectable expression in non-tumor, non-germline tissues;
No major safety concerns were identified for MAGE-A4 SPEAR T-cells using Adaptimmune’s extensive in vitro preclinical testing platform;
MAGE-A4 SPEAR T-cells displayed strong cytotoxicity towards MAGE-A4+ melanoma and NSCLC cell lines, and;
These data will support filing of an IND, with submission planned for early 2017.
Second Generation SPEAR T-cell Engineered to Overcome TGF-Beta Tumor-mediated Immunosuppression
In a poster presentation entitled, "Engineering 2nd generation SPEAR T-cells to overcome TGF-Beta-mediated immunosuppression for adoptive cell therapy," Andrew Gerry, Ph.D. of Adaptimmune presented preclinical data regarding the development of this second generation SPEAR T-cell.

NY-ESO SPEAR T-cells have shown promising activity in clinical trials for both solid and liquid tumors. However, the depth and durability of response may potentially be affected by inhibitory factors in the tumor microenvironment;
One such factor is an inhibitory cytokine known as TGF-Beta that inhibits many T‑cell functions including proliferation, cytotoxicity, and cytokine production. Truncation of the intracellular signaling domain of the TGF-Beta receptor produces a dominant negative form of this receptor (dnTGFBetaRII), and data from the literature indicate that expression of this dominant negative receptor negates the inhibitory effects of TGF-Beta;
Adaptimmune engineered a second generation NY-ESO SPEAR T-cell co-expressing dnTGFBetaRII to produce resistance to TGF-Beta immunosuppression, and;
Data indicate that these second generation NY-ESO SPEAR T-cells co-expressing dnTGFBetaRII are resistant to inhibition by TGF-Beta in vitro.
Case Study Demonstrating Long-term SPEAR T-cell Persistence and Maintenance of Tumoricidal Activity
In a poster presentation entitled, "Case Report: Specific Peptide Enhanced Affinity Receptor T-Cells (SPEAR T-cells) demonstrate long-term persistence and both in vivo and ex vivo tumoricidal activity," Samik Basu M.D. and Gareth Betts Ph.D., both of Adaptimmune, presented translational data from a single patient who was treated in October 2013 in Cohort 1 of the ongoing study of NY-ESO SPEAR T-cell in synovial sarcoma. This patient was included in analyses that have been previously presented.

Data indicate that NY-ESO SPEAR T-cells have long-term persistence as they were readily detectable in the patient’s peripheral blood at 28 months post-infusion;
These cells exhibited markers of long‑term, self-renewing memory T-cells with minimal expression of phenotypic markers of exhaustion;
NY-ESO SPEAR T-cells retained tumoricidal activity when they were evaluated ex vivo against tumor targets exhibiting substantial killing of NY-ESO-1+ cells without additional re-stimulation, and;
Mechanisms underlying tumor progression remain under investigation and broadly appear to be related to T-cell exclusion by tumor, supporting consideration of rational combination study designs.

On November 11, 2016 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that a poster featuring preclinical data related to its tetravalent anti-GITR agonist antibody, FPA154, was presented today at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in National Harbor, Maryland (Press release, Five Prime Therapeutics, NOV 11, 2016, View Source [SID1234516495]). Poster #175 titled, "Novel tetravalent anti-GITR antibody is a potent anti-tumor agent in vivo," is available at View Source

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"With our lead anti-GITR candidate, FPA154, now in pre-IND enabling studies, we are pleased to highlight our first preclinical data supporting the development and differentiation of this novel, tetravalent antibody," said Luis Borges, Ph.D., Senior Vice President of Research, at Five Prime. "In vitro data demonstrates that our tetravalent antibody has agonistic activity in the absence of Fc-mediated crosslinking. In vivo, the antibody has potent anti-tumor activity in various murine tumor models and it confers long-term anti-tumor immunity. It alters the ratio of Tregs to effector T cells, creating a favorable environment for an effective anti-tumor immune response. These findings suggest the potential for FPA154 to activate T cell immunity against various tumors and we are working to move this program rapidly toward clinical development."

FPA154 has been designed using single-domain antibodies in a tetravalent format, inducing effector T cell stimulation in vitro that is superior to a conventional bivalent antibody format and conferring agonistic activity even in the absence of Fc-mediated crosslinking. The poster features preclinical data provided by a mouse-reactive surrogate molecule that demonstrate potent inhibition of tumor growth in mouse tumor models:

Potent anti-tumor activity following a single dose: A single dose of tetravalent anti-GITR significantly inhibited tumor growth in multiple models including CT26 and MC38. Treatment was capable of inducing complete tumor rejection, and activity was observed at doses as low as 0.08 mg/kg in both models.

Fc-independent activity: Tetravalent anti-GITR antibody retained partial tumor growth inhibition activity even in the absence of Fc-mediated crosslinking or effector function, whereas a conventional bivalent antibody (DTA-1) required Fc function.
Pharmacodynamic responses: Tetravalent anti-GITR antibody treatment reduced the number of T cells in the peripheral blood 3 days post-treatment. In the tumor, Treg and conventional CD4 T cells decreased, but CD8 T cell numbers were maintained. This resulted in a ratio of CD4 and CD8 effector T cells to Treg that created a favorable environment for an effective anti-tumor immune response.

Induction of long-term immunity: Mice that eliminated CT26 tumors in response to tetravalent anti-GITR were resistant to tumor regrowth upon re-challenge with the same tumor, but not to an antigenically-unrelated tumor.

On November 11, 2016 CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, reported a poster with updated interim results from its on-going Phase 1b/2 trial of aldoxorubicin in combination with ifosfamide/mesna in patients with advanced sarcomas at the 2016 Annual Meeting of the Connective Tissue Oncology Society (CTOS) being held in Lisbon, Portugal (Press release, CytRx, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221789 [SID1234516494]).

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Forty-two patients have been enrolled to date and 36 were evaluable as of the data cutoff. Of the 36 evaluable patients receiving either 170mg/m2 (n=7) or 250mg/m2 (n=29) of aldoxorubicin plus ifosfamide and mesna, 14 of 36 (39%) achieved a partial response of the target lesion by RECIST 1.1 criteria, 21 of 36 (58%) had stable disease, and one patient had progressive disease. As previously reported in October at the 2016 ESMO (Free ESMO Whitepaper) Congress, median progression-free survival has not yet been reached. Dose-limiting toxicities were not observed in either cohort, and no clinically significant cardiac toxicities were seen. The most common Grade 3 or 4 adverse events were neutropenia (71%), anemia (54%), thrombocytopenia (17%) and febrile neutropenia (14%). There were nine treatment-related serious adverse events, and no treatment-related deaths. The trial has been expanded to allow continued enrollment of additional sarcoma patients at the 250 mg/m2 dose of aldoxorubicin with ifosfamide and mesna.

"The CTOS annual meeting is the preeminent medical conference focused on sarcomas and provides an opportunity to update the international sarcoma community with the latest results for aldoxorubicin, said Sant Chawla, M.D., F.R.A.C.P., the trial’s principal investigator and Director of the Sarcoma Oncology Center in Santa Monica, California. "Our poster highlights that nearly 40% of the sarcoma patients receiving the combination of aldoxorubicin with ifosfamide and mesna achieved a partial response of the target lesion by RECIST criteria, and half of those had greater than 50% shrinkage of their tumors. This is important because it allowed some patients who initially could not have surgery to become eligible for surgery."

The Phase 1b/2 clinical study is a single-center trial that has enrolled 42 patients to date with locally advanced, unresectable, and/or metastatic soft tissue sarcoma, intermediate-grade or high-grade chondrosarcoma or osteosarcoma. In the dose escalation phase, patients received either 170mg/m2 or 250mg/m2 of aldoxorubicin in combination with up to a 14-day continuous infusion of ifosfamide (1g/m2/day) plus mesna over a 28-day cycle. Up to six cycles of ifosfamide/mesna with aldoxorubicin can be administered, and aldoxorubicin may be continued until tumor progression or unacceptable toxicity occurs. The expansion phase is enrolling patients at the 250mg/m2 dose of aldoxorubicin and will allow for patients that had received prior chemotherapy to be included. The primary endpoint of the study is safety, and secondary endpoints include overall response rates and progression-free survival.

About Aldoxorubicin

Aldoxorubicin is a rationally-engineered cytotoxic which combines doxorubicin, a widely used chemotherapeutic agent, with a novel linker molecule that binds directly and specifically to circulating albumin, the most abundant protein in the bloodstream. Protein-hungry tumors concentrate albumin, which facilitates the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. Typically, doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Using this acid-sensitive linker technology, aldoxorubicin delivers greater doses of doxorubicin (3 ½ to 4 times). To date, there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of doxorubicin in excess of 5,000 mg/m2. Aldoxorubicin is the first-ever single agent to show superiority over doxorubicin in a randomized global Phase 2b clinical trial in first-line STS.

On November 11, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on discovering and developing novel small molecule drugs directed against tumor metabolism and tumor immunology targets for the treatment of cancer, reported that data for its drug candidates CB-839, the company’s novel glutaminase inhibitor, and CB-1158, the company’s novel arginase inhibitor, will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2016 Annual Meeting, which is being held from November 9-13, 2016 in National Harbor, Maryland (Press release, Calithera Biosciences, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221726 [SID1234516491]).

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"Both CB-839 and CB-1158 have the distinction of targeting metabolic and immune checkpoints which we believe, through rational combinations, have the potential to be transformational in the treatment of cancer. CB-839 and CB-1158 are each in clinical trials with cohorts planned in combination with approved immunotherapy agents," said Susan Molineaux, Ph.D., President and Chief Executive Officer of Calithera. "We are pleased that CB-1158 shows significant pharmacodynamic effects in patients at the first dose level tested."

Preclinical CB-839 data will be presented in a poster titled, "Targeting tumor glutamine metabolism with CB-839 enhances the efficacy of immune checkpoint inhibitors," by Andy MacKinnon, Ph.D., Calithera Biosciences (Poster #230). Included in the presentation are data that provide further insights into the mechanism by which inhibition of glutaminase by CB-839 enhances T-cell activation and increases the anti-tumor activity of anti-PD-L1 and anti-PD-1 antibodies. Glutamine deprivation during T-cell activation was shown to block Myc expression and Myc-driven metabolic re-programming, and to promote expression of T-cell suppressive markers such as BTLA, CTLA-4, PD-1, and CD73. In two syngeneic animal models, CT26 (colon cancer) and B16 (melanoma) the combination of CB-839 and anti-PD-L1 or anti-PD-1 showed significantly enhanced anti-tumor activity over checkpoint inhibition alone resulting in increased tumor regressions in the CT26 model. Depletion of CD8+ T-cells from these tumor-bearing animals reversed the anti-tumor effects of the combination, confirming an immune-mediated mechanism of action.

CB-1158 data will be presented in a poster titled, "Arginase inhibitor CB-1158 alleviates immunosuppression and enhances anti-tumor responses as a single agent and in combination with other immunotherapies," by Amani Makkouk, Ph.D., Calithera Biosciences (Poster #231). Arginase is expressed in myeloid derived suppressor cells (MDSCs) and exerts an immunosuppressive effect on T-cells and NK cells by depleting arginine and blocking activation. Tumor cell infiltrates in patients with solid tumor cancers contain significant numbers of arginase-expressing MDSCs; as a result, these patients have increased levels of plasma arginase and decreased levels of plasma arginine compared to healthy individuals. CB-1158, a highly selective, orally bioavailable, small molecule inhibitor of human arginase with nanomolar potency, has single agent immune-mediated efficacy in multiple syngeneic animal models. Inhibition of tumor growth was accompanied by an increase in the local concentration of arginine, and the induction of multiple pro-inflammatory changes in the tumor microenvironment. Treatment with CB-1158 also enhanced the anti-tumor activity of adoptive T-cell therapy, checkpoint blockade and chemotherapy in these animal models. CB-1158 is currently being tested in a Phase 1 clinical trial in patients with solid tumors. Three patients in the first cohort were treated with 50 mg of CB-1158 twice daily. This dose was well-tolerated and was pharmacologically active, resulting in sustained elevation of arginine in the plasma of all three patients. The trial is continuing to enroll patients to complete the dose escalation phase of the study, to be followed by combination studies with a PD-1 antibody.

In addition, two posters describing trial design will be presented during the "Clinical Trials in Progress" session:

CX-1158-101: A first-in-human phase I study of a small molecule inhibitor of arginase (CB-1158) as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients with solid tumors

Presenter: Siqing Fu, M.D., Ph.D., University of Texas, MD Anderson Cancer Center, Poster #155

CX-839-004: A phase I/II study of the safety, pharmacokinetics, and pharmacodynamics of the glutaminase inhibitor CB-839 combined with nivolumab in patients with renal cell carcinoma, melanoma, and non-small cell lung cancer

Presenter: Elaine Lam, M.D., University of Colorado, Denver, Poster #166