Cell Medica’s Antigen-Specific T-cells for Lymphoma

Cell Medica, a London-based biotech company, raised $78MM in a Series B financing with several accomplished biotech investors on the strength of data from its clinical trials in patients with EBV (Epstein Barr Virus) associated lymphomas.

CMD-003 is an autologous immunotherapy comprised of the patient’s own T-cells that recognize Epstein-Barr Virus Latent Membrane Proteins (EBV-LMPs). The therapy is being developed in cooperation with the Center for Cell and Gene Therapy at Baylor College of Medicine (CAGT). Cell Medical licensed the technology and optimized the autologous T cell preparation process. It is now hoping to confirm the results seen previously by Baylor in a study utilizing its new manufacturing process.

In its study, Baylor reported 11 complete responses out of 21 patients with relapsed or resistant lymphoma. And 28 of 29 high-risk or multiple-relapse patients remained in remission at a median of 3.1 years. The results were published in the Journal of Clinical Oncology earlier this year.

EBV is associated with 15% – 20% of lymphomas, more than 90% of nasopharyngeal carcinomas and about 10% of gastric cancer. Within the lymphoma group, EBV association varies significantly by subtype. Association ranges from up to 100% for extranodal NK/T cell lymphoma, 20% to 90% for Burkitt’s lymphoma depending on region, over 50% for angioimmunoblastic T cell lymphoma and 20% – 50% for Hodgkin Lymphoma.

EBV

Latent membrane protein 1 (LMP1) consists of cytoplasmic amino-terminal and carboxy-terminal domains linked by six transmembrane sequences with no significant extracellular domain. The carboxy-terminal domain has extensive functional homology, but no significant sequence homology, with CD40. Both LMP1 and CD40 contain consensus tumour-necrosis-factor-receptor-associated factor (TRAF)-binding domains and interact with multiple members of that family. The downstream signalling from LMP1 and CD40 causes activation of nuclear factor-kappaB (NFkappaB). LMP1 and CD40 have also been shown to interact with Janus-activated kinase 3 (JAK3) and signal transducers and activators of transcription (STATs), and to activate the activator protein 1 (AP-1) transcription complex through the c-Jun N-terminal kinase (JNK) signalling pathway. The net result is that both LMP1 and CD40 signalling rescues B cells from apoptosis and drives their proliferation. Interestingly, LMP1 and CD40 do not interact with exactly the same sets of molecules, indicating that the signalling pathways might differ in some aspects. For example, CD40 binds TRAF6 but LMP1 does not. Conversely, LMP1 binds TNFR-associated death domain protein (TRADD), which is usually associated with death signals, but not in the case of LMP1. Additionally, CD40 activates NF-kappaB primarily through the binding of TRAF2 to its consensus TRAF-binding sequence (Pro-Xaa-Gln-Xaa-Thr; PXQXT), whereas the PXQXT domain seems to be relatively unimportant for NF-kappaB activation by LMP1. Instead, it is the recruitment of TRAF2 by the TRADD-binding domain that is crucial for NF-kappaB activation. IKK, inhibitory kappaB kinase; NIK, NF-kappaB-inducing kinase; RIP, receptor-interacting protein. http://www.nature.com/nri/journal/v1/n1/fig_tab/nri1001-075a_F1.html

Clinical trials in extranodal NK/T cell lymphoma are ongoing. Blood is taken from the patient with EBV+ cancers, and the EBV-reactive CTLs (cytotoxic T-cells) are expanded and prepared for reinfusion. In the Phase 2 extranodal NK/T cell lymphoma study, treatment consists of two injections of 2x10E7 cells/m2 given on Days 1 and 15 intravenously via a peripheral or central line over a 1 to 10 minute period. Subjects without clinical signs of disease progression at the week 8 assessment are eligible for up to 3 additional injections of 2x10E7 cells/m2 administered at week 8, month 3 and month 6.

 

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