Engineered T-Cell Receptor and T-Cells: independent, but also complementary tools for immuno-oncology with great prospects

STUTTGART, Germany I March 12, 2015 I 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 (tumor) cells by human leukocyte antigen (HLA) molecules and are not druggable by conventional antibody technologies. As the industry is in need of new targets, such a pool of intracellular targets which are validated, disease-specific and intellectual property (IP)-free, has attracted great interest by Big Pharma companies as reflected by several major collaborations.

To make use of the TCR in a therapeutic, the TCR has to be combined with an effector moiety either by recombinant DNA technology or by cellular engineering. Big Pharma has accepted and adopted recombinant antibody technologies over the last one or two decades, but is hesitating to enter the field of personalized (autologous) cell therapy. Thus, a preferred option for a TCR therapeutic is to fuse a monoclonal TCR with a single-chain variable fragment (scFv) against CD3 to recruit T cells in vivo and, thereby, exert the antitumor effect. British biotechnology company Immunocore has developed such a technology called ImmTAC and is employing it to create monoclonal TCR-scFv constructs. The first candidates from collaborations with Big Pharma are now in non-clinical development.

While ImmTACs make indirectly use of T-cells by recruiting them in vivo, the alternative, cellular approach is to transduce ex vivo autologous T-cells with the TCR of choice and additional signaling molecules, expand the selected T cell population and reinfuse the cells to the patient. Several companies are already in early clinical trials with TCR-transduced T cells, but the major differentiating factor between them is the target against which the TCR is directed. A number of intracellular cancer antigens are publicly known and have already been used for antigen-specific cancer immunotherapy. Typical targets are Wilms tumor 1 (WT1), cancer testis antigen NY-ESO-1, MAGE-A3 or PRAME. These targets are not IP protected and, thus, subject to competition. On the contrary, Immunocore and cell therapy sister company Adaptimmune have developed a proprietary TCR target discovery engine which provided them with a pool of novel TCR targets.

Both Immunocre and Adaptimmune have raised substantial funds by partnering and financing rounds to ensure further corporate development.

The power of T cells can also be directed against conventional targets on the surface of tumor cells. Again, there are two alternative therapeutic modalities: a recombinant biologic or a cell therapeutic. One such recombinant molecule has been approved by the US FDA in December 2014 and is directed against the B cell target CD19. Blinatumomab is a recombinant bispecific T cell engaging (BiTE) molecule consisting of two scFv moieties, one directed against the tumor target CD19 and the second directed against CD3 on T-cells to recruit them in a targeted manner to the tumor cells. Blinatumomab (Blincyto) from Amgen is used for treatment of relapsed/refratory (r/r) acute lymphoblastic leukemia (ALL) and will cost US$ 178,000 which includes two therapy cycles.

Leveraging the power of T cells by cellular and recombinant immunotherapeutics

A direct way to bring T-cells specifically in contact with tumor B cells, is to transduce ex vivo autologous T-cells with a scFv against CD19 plus additional signaling molecules and transfuse the cells back into the patient. Several such „chimeric antigen receptor“ (CAR) transduced autologous T cell constructs have been evaluated in small clinical trials of r/r ALL with impressing results of 80% or higher response rates. These results have triggered a lot of enthusiasm among investors and have encouraged several leading cancer institutions active in the CAR T-cell field, to spin-off their technology into new companies for further development and commercialization.

However, the early clinical trials also have revealed challenges for the success of further CAR T-cell therapies regarding efficacy, safety and manufacturing.

The report „Engineered TCR and CAR Immunotherapeutics 2015: A comparative analysis of the landscape of and business opportunities with TCR and CAR antibodies, T cells, NK cells, TILs, DLIs & DLIs“ released by La Merie Publishing brings you up-to-date regarding key players, key technologies, TCR and CAR immunotherapeutic projects, business deals and private and public financing rounds. The report analyzes the TCR and CAR immunotherapeutic pipelines and stakeholders in the field, especially among Big Pharma/Biotech and technology companies. This study highlights the value of TCR and CAR immunotherapeutics in terms of partnering economic conditions, private financing rounds and (initial) public offerings with the resulting market capitalization of companies. The report also describes the challenges and limitations and identifies solutions provided by new technologies which offer tremendous business opportunities.

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SOURCE: La Merie Publishing