Engineered TCR and CAR Immunotherapeutics 2015:

Transcription

1 : A comparative analysis of the landscape of and business opportunities with TCR and CAR antibodies, T cells, NK cells, TILs, DLIs and CTLs released by La Merie Publishing on March 10, 2015 La Merie Publishing Sophienstrasse 8 D Stuttgart info@lamerie.com Copyright 2015 La Merie Publishing This management report is published by La Merie Publishing. All rights reserved. Reproduction or redistribution of this management report in any form for any purpose is expressly prohibited without the prior written consent of La Merie Publishing. The views expressed in this management report are those of the authors, not of La Merie Publishing. La Merie Publishing accepts no liability for the accuracy or completeness of the information, advice or comment contained in this management report nor for any actions taken in reliance thereon. While information, advice or comment is believed to be correct at the time of publication, no responsibility can be accepted by La Merie Publishing for its completeness or accuracy.

2 Introduction The T cell receptor and T cells are independent, but at the same time complementary tools for immunotherapy of cancer. The T cell receptor (TCR) has emerged as a means to target peptide antigens derived from intracellular proteins in a major histocompatibility complex (MHC) dependent manner. These peptide antigens are presented on the surface of cells by human leukocyte antigen (HLA) molecules. When a monoclonal TCR (mtcr) is combined with an effector moiety, the resulting therapeutic modality can target intracellular tumor antigens and exert antitumor activity via the effector moiety which can be an engineered T cell or an antibody fragment for recruitment of T cells (anti-cd3 single-chain variable fragment: scfv) or a cytokine (e.g. interleukin-2). In some cases, TCR-like antibodies have been discovered and are in development, but so far no robust technology has been validated for discovery and creation of TCR-like antibodies. Bispecific TCR-like antibodies are not in development. The classical way to target antigens on the surface of tumor cells is based on antibodies or any other construct exerting a receptor-ligand interaction. The first bispecific antibodies (catumaxumab and blinatumomab) have already been approved, both of them have a targeting moiety (CEA or CD19, respectively) and a T-cell recruiting effector moiety (anti-cd3 scfv). T- cells can also be engineered to express a scfv for targeting, called the chimeric antigen receptor (CAR) which further includes hinge, transmembrane domain, the essential signaling domain CD3zeta and additional one or two co-stimulatory signalling domains (mostly CD28 and/or 4-1BB/CD137). At present it is not known whether T cells engineered for specific targeting either via the TCR or the CAR are superior to conventional bispecific antibody constructs and the newly emerging class of bispecific ImmTAC (Immune mobilising mtcr Against Cancer) molecules. Intra-cellular Targets Cell surface targets Cellular TCR T Cells CAR T Cells Recombinant Bispecific TCR-anti-CD3 (e.g. ImmTACs) Bispecific antibodies (incl. anti- CD3) March /201

3 burden prior to T cell transfer, and determining if the treatment is associated with tumor lysis syndrome. Interim results from the study were presented at ASH 2014 (Press Release Dec 8, 2014). In patients receiving defined composition products, responses were observed in 6/10 (60%) evaluable NHL patients, and 2/2 evaluable CLL patients, complete remission occurred in 11/11 (100%) patients and complete molecular remissions occurred in 9/11 (82%) patients with ALL. A subset of NHL patients tested in whom CAR T cells became undetectable developed a T cell immune response to sequences in the murine CD19 specific single-chain variable fragment (scfv) component of the CAR transgene. Severe CRS was observed in 3/13 (23%) ALL patients, including one death, and in 0/14 evaluable NHL/CLL patients. Grade 3 delirium was observed in one patient with CLL. With JCAR014, even in patients with limited cell expansion, Juno has seen significant antitumor responses, suggesting that CD8+ central memory T cells may have potential potency advantages. However, the company believes that the manufacturing approach for JCAR014 has certain limitations that appear to affect cell expansion and cell persistence in some patients, which can limit the durability of response in those patients. Juno plans to continue enrolling patients in the ongoing Phase I/II trial in 2015 in order to explore various treatment strategies to improve the expansion and persistence of the CAR T cells in the body. However, given the progress of Juno s other CD19-directed product candidates, Juno does not plan to proceed to registration trials with JCAR KTE-C19 Under the CRADA with the NCI, a CD19-targeting CAR T cell product candidate has been evaluated by the NCI in exploratory phase I/II clinical trials at the Surgery Branch of the NCI. Due to promising results of the clinical studies at the NCI, Kite Pharma has selected KTE-C19 as the first autologous T cell product candidate for commercial development. As a prerequisite for commercial development, Kite Pharma has selected the contract manufacturing organization (CMO) Progenitor Cell Therapy (PCT), a subsidiary of NeoStem, with facilities in California and New Jersey, USA (Press Release Jan 9, 2014). In connection with March /201

4 signals of clinical efficacy (Press Release Dec 8, 2014; Bar, 2014). 13 out of 15 patients were still alive as of November 10, 2014 with follow-up as long as 18 months and the genetically engineered TCR T cells remained detectable in 12 out of 15 patients, with follow-up ranging from five to 368 days from their last infusion. There have been no observed events of severe cytokine release syndrome in these patients. Overall, the interim results show an acceptable safety profile and encouraging enough anti-tumor activity to continue and expand clinical studies. 4.3 CD19 CAR T Cells CAR T Cells targeting CD19 are the CAR T cell product candidates getting the most attention due to stunning results in treatment of pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Impressive response rates of higher than 80% have been reported for this patient population across different CAR designs, trial designs and institutions (Maus, 2014). Results with CD19 CAR T-Cells in other B-cell malignancies such as chronic lymphocytic leukemia (CLL) or Non-Hodgkin s lymphoma (NHL) are not as impressive. The two most advanced CD19 CAR T-Cell product candidates from Novartis & UPenn (CTL019) and from Juno Therapeutics & Memorial Sloan Kettering Cancer Center (JCAR015) have received Breakthrough Therapy designation from the US FDA. Novartis plans to submit regulatory documentation in 2016 and Juno expects potential approval in 2017 which would givem them a competitive edge in commercialization over competitors in the USA. Table 4 summarizes commercial CD19 CAR T Cell developments over the globe. Table 4: Pipeline of CD19 CAR T-cell product candidates from Companies 1/4 Product Name CTL019; CTL-019; CART-19 Target / Mechanism of Action CD19 targeting Class of Compound Autologous T cells lentivirally transduced to express CD19 CAR with tandem TCR zeta and 4-1BB costimulatory domains Company Indication R&D Stage Novartis & University of Pennsylvania (vector from Lentigen) Pediatric and adult patients with r/r ALL r/r CLL; NHL incl DLBCL Multiple myeloma after ASCT II II I March /201

5 Very recently, Lion announced that its existing CRADA with the National Cancer Institute (NCI) focused on metastatic melanoma has been amended to include four new tumor indications for TIL therapy (Press Release Jan 26, 2015). Under the modified terms of the CRADA, the NCI has granted Lion the rights to develop TIL therapy for the treatment of bladder, lung, triple-negative breast and HPV-associated cancers (including cervical and head and neck cancers), in addition to the company's current programs in metastatic melanoma. Furthermore, the NCI has agreed to provide Lion with samples of all tumors covered by the amendment for performing studies related to improving TIL selection and/or TIL scale-out production and process development. To fund the NCI's expanded development efforts and support, Lion will increase its annual payments to NCI from US$ 1 million to US$ 2 million. Lion s lead product showed strong phase II data in a phase II investigator-sponsored study in stage IV metastatic melanoma conducted at the NCI (Rosenberg, 2011). Tumor infiltrating lymphocytes (TILs) originating from the patient s own tumor sample have the strong advantage of recognizing de novo multiple self and mutated antigens (Lion Presentation Jan 2015). In 2nd and 3rd line therapy of metastatic melanoma, TILs showed an impressive survival benefit with durable remissions regardless of prior therapies. 19 of 20 complete responders were relapse free at 7 to more than 10 years after adoptive cell therapy. An overall response rate of 46-49% was consistently achieved at four different clinical sites in a total of 136 metastatic melanoma patients. Lion has been cleared by the FDA to conduct a kind of bridging phase II study in 20 melanoma patients to validate its commercial scale and process GMP manufacturing service facility at Lonza. A phase III study of TILs (named LN-144) manufactured by the new process is planned to commence in Lion is negotiating with the NCI exclusive license agreements regarding TILs for the indication melanoma; 2nd generation TILs also for melanoma; and for TILs used for treatment of other solid tumors. It appears that the NIC is already clinically evaluating 2nd generation TILs for melanoma as interim phase II data are expected by end of Eventually, Lion has obtained an exclusive, worldwide license from the National Institute of Health (NIH) to certain patents to develop and commercialize TIL therapy in the treatment of metastatic melanoma (Press Release Feb 10, 2015). March /201

6 2013). Immunocore received an initiation fee of between US$ 10 and 20 million per program and is eligible to receive in excess of US$ 300 million in development and commercial milestone payments for each target program and significant tiered royalties Servier French pharmaceutical company Servier signed a strategic collaboration agreement with Cellectis to develop and commercialize novel product candidates targeting leukemia and solid tumors (Press Release Feb 18, 2014). The partnership covers the development and potentially the commercialization of Cellectis lead product candidate, UCART19 for treating various types of leukemias and lymphomas. The agreement also includes research, development, and potentially the commercialization of five other product candidates targeting solid tumors. Cellectis develops allogeneic, off-the-shelf universal chimeric antigen receptor T-cells (UCARTs) for treatment of hematologic malignancies and solid tumors. The lead program UCART19 is scheduled to enter phase I testing in the second half of Table 25: Major terms of collaboration between Cellectis and Servier Licensor Cellectis Licensee Servier Source of information Press Release February 18, 2014 Licensor technology Allogeneic off-the-shelf universal chimeric antigen receptor T-Cell (UCART) technology Territory Worldwide Field Oncology (hematologic malignancies and solid tumors) Scope Exclusive option for a license Upfron payment US$ 10 mln Number of projects UCART19 for B-cell malignancies and five solid tumor targets Milestone payments per product US$ 140 mln per project x 6 = US$ 840 mln Maximum total value US$ 850 mln Royalties Royalties on sales of each commercialized product Cellectis is responsible for the R&D through the end of Phase I. Servier may exercise an exclusive worldwide option for a license on each product candidate developed under the agreement. Upon exercising each option, Servier will be responsible for taking over the programs. March /201

7 Bossi G, Baker D, Adams K et al. ImmTACs: bi-specific TCR-anti-CD3 fusions for potent re-directed killing of cancer cells Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Cancer Res 2014a;74(19 Suppl):Abstract nr 670. doi: / am Bossi B, Buisson S, Oates J et al. ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells Cancer Immunol Immunother 2014; 63: Chmielewski M, Hombach AA, Abken H Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered wiht an inducible cytokine to modulate the tumor stroma Immunol Rev 2014; 257: Chono H, Tahara K, Nukaya I et al. Engineering of CD19-CAR T cells from non-hodgkin lymphoma patients in a closed system in combination with retronektin/okt3 stimulation 56th Annual Meeting of the American Society of Hematology (ASH); San Francisco, CA, USA; December 6-9, 2014: abstract 2446 Cohen M, Reiter Y T-cell receptor-like antibodies: targeting the intracellular proteome therapeutic potential and clinical applications Antibodies 2013; 2: Dao T, Liu C, Scheinberg DA Approaching untargetable tumor-associated antigens with antibodies OncoImmunology 2013; 2: e24678 Dao T, an S, Veomett N et al. Targeting the intracellular WT1 oncogene product with a therapeutic human antibody Sci Transl Med. 2013; 5(176):176ra33 March /201