1. Do cell therapies represent a breakthrough in cancer treatment?
Mario Kuttke: It is really amazing how adoptive cell therapy (ACT), a form of cancer immunotherapy, has evolved so rapidly in the last decade. A substantial amount of R&D resources have been dedicated to ACT, mostly involving the transplant of autologous immune cells, including tumor-infiltrating lymphocytes (TILs). The basis for ACT is the finding that immune cells play an essential role in recognizing and destroying tumors.
The question is how to engineer “smarter” immune cells that are more effective in this regard. This opens the door to treatments for a variety of cancers that have long been considered untreatable with current immunotherapies. ACT products differ from classical pharmaceutical drugs as they provide a panel of cellular capacities upon activation, including active migration into the tumor, release of effector molecules and cytokines, direct anti-tumor cytotoxicity, immune cell proliferation, long-term persistence, and immunological memory. Therefore, ACT has huge potential to augment the standard of care for many cancers.
2. Besides CARs, which approaches possess the power to efficiently eliminate tumor cells?
Mario Kuttke: Chimeric antigen receptor (CAR) T cells have reached the clinical landscape for therapy of blood cancers. CARs are hybrid receptors, currently genetically constructed and stably transferred to T cells. Unlike natural T cell receptor (TCR) based immune cell communication, CAR T cells show target recognition in an MHC (major histocompatibility complex)-independent manner. The most efficacious results to date have been obtained in blood cancers using CD19-directed CAR T cell therapy and have already led to commercial approvals by the FDA and EMA. CAR T cell technology is being explored for the treatment of solid tumors but limited clinical activity has been delivered to date.
What we pursue at invIOs is to achieve clinical benefit in various solid tumors applying a different ACT approach that utilizes the patient’s own peripheral blood mononuclear cells (PBMCs). Unlike T-cell restricted CAR approaches, PBMCs comprise a variety of immune cells that are known to be relevant in anti-tumor innate and adoptive immune responses. Moreover, we target Cbl-b, a novel intracellular immune checkpoint. By blocking Cbl-b in PBMCs we achieve antigen-dependent immune cell activation, cytokine production and killing of tumor cells. This approach – invIOs’s project APN401 – is currently in the clinic in a phase 1b trial in patients with advanced-stage solid tumors.
Currently, the immunotherapy toolbox is rapidly expanding and improving, and the future promises further breakthroughs in the ACT field. Two formidable challenges are the heterogeneity of the tumor microenvironment (TME) and the multiplicity of tumor (immune) escape mechanisms. One challenge to finding a universal cancer treatment is the heterogeneity between different tumors and within one patient as a result of genetic evolution as the cancer progresses, which gives rise to novel and therapy-resistant clones (acquired resistance). Personalized and precision medicine, which aims to tailor treatments to tumor-specific cellular or molecular characteristics, has recently become the mainstay of oncological therapy. TIL-ACT bypasses the issue of interlesional heterogeneity by utilizing autologous TILs, in other words the patient’s existing antitumor repertoire. However, TILs come with roadblocks. One is that these T cells must first be activated before they can destroy tumor cells. Another is that TILs might not exist in sufficient quantity making ex vivo expansion necessary. Again, similar to the approach that invIOs is taking with APN401, blocking Cbl-b in TILs releases the brake on T cells, and the now re-activated TILs are able to contribute to anti-tumor immunity.
3. Will ACT with a multiplicity of immune cells lead to pioneering treatments for solid tumors in the future?
Mario Kuttke: The ultimate goal of ACT as a cancer treatment is to create an optimal personalized cellular product, ideally one that is solely reactive against the tumor. In previous decades, R&D of ACTs such as CARs and TILs undertook efforts to improve efficacy and manage toxicities. So, what are the future prospects for cell therapy? I believe there are two directions: First, to deliver a more potent cell product which would prolong survival and quality of life for patients, including those with hard-to-treat and refractory/relapsed solid tumors. Second, to overcome constraints around manipulation and manufacturing of the cells in order to reduce complexity, logistics and finally duration of handling.
InvIOs’s novel cell therapy, APN401, which precisely targets Cbl-b in Peripheral Blood Mononuclear cells (PBMCs) – containing cells such as T, Natural killer (NK) and Antigen-presenting cells (APCs) but also B lymphocytes – has become a promising clinical-stage candidate that has the potential to overcome many constraints seen in other ACTs. APN401 may also become a synergistic partner for other treatment modalities that cannot individually overcome the immune-suppressive TME. Moreover, APN401 has a short needle-to-needle time, reducing the manipulation time and rapidly delivering a personalized ACT product that uses recent immune cells without cryopreservation.
Another exciting approach where Cbl-b targeting may help to re-activate tumor-reactive lymphocytes are TILs, such as in invIOs’s project INV441. TILs are a heterogeneous cell product that recognize multiple tumor-antigens. Blocking Cbl-b in TILs may allow for a potent therapy which can be delivered directly to the tumor site in, for example, glioblastoma. INV441 is currently in the pre-clinical stage.
About MARIO KUTTKE – Head of Cell Therapy at invIOs, Vienna
- PhD in immunology
- Former scientist at Research Institute of Molecular Pathology and Medical University of Vienna
- Proven track record of IO research in academia and the pharmaceutical industry