Malignant tumors can be detected by natural killer (NK) cells and T-cells of the immune system because they display tumor-specific antigens, also called neoantigens, which result from mutations in the tumor genome, and are recognized as non-self. Tumor-associated antigens (TAAs) are proteins more abundant on the surface of cancer cells compared to normal cells and can initiate a T-cell anti-cancer response. TAAs are shared by a subgroup of patients but neoantigens are unique to individual patient tumors. Tumors acquire certain characteristics that help them evade immune detection and the tumor micro-environment creates an immunosuppressive network.
To enhance the ability of T-cells and NK cells to kill cancer cells, immune cells are generated with modified T-cell receptors (TCRs) or expressing chimeric antigen receptors (CARs) designed to target various tumor antigens and neoantigens. Either the patient's own cells (autogeneic) or allogeneic cells are used to generate these types of immunotherapies.
Immune checkpoint proteins are involved in controlling immune responses. Cancers can activate immune checkpoint mechanisms resulting in suppression of the immune system’s anti-tumor response. Immune checkpoint inhibitors are a type of immunotherapy which utilises antibodies to block immune checkpoint proteins.
Tumors are thought to perpetuate their survival by reprogramming the metabolism of the host. Since increased metabolic stress can decrease antitumor T-cell immune response some cancer immunotherapy strategies aim to normalize metabolic stress.
Abbvie - Using Calibr's switchable CAR-T platform against solid tumors and other cancers
Calibr - modular ‘switchable’ CAR-T cell that uses antibody-based switch molecules, working towards universal CAR-T based treatments for hematological and solid cancers
Allogene Therapeutics - Using UCART19 against CD19-expressing hematological malignancies, acute lymphoblastic leukemia
Atara Biotherapeutics- Off-the-shelf, allogeneic T-cell immunotherapy
Bellicum Pharmaceuticals - GoCAR-T cells incorporates an activation switch needing both the target cancer cells and rimiducid
Cellectis - creating “off-the-shelf” allogeneic products called universal chimeric antigen receptor T-cells (UCART)
Cell Design Labs - Throttle™, CAR-T cells with small molecule control of an “on/off” switch and synNotch™, a synthetic gene expression system in CAR-T cells for better tumor recognition and specificity
Celularity - CAR constructs for allogeneic CAR-T/NK products
Celyad - CAR-T NK cell-based immunotherapies for cancer
Janssen Biotech - Experimental CART-cell therapy LCAR-B38M for myeloma
Kite Pharma - CAR-T cell therapy called Yescarta U.S. FDA approved for treatment of relapsed or refractory large B-cell lymphoma
Nanjing Legend Biotech
Novartis - U.S. FDA approved CAR-T cell therapy, Kymriah, which uses self-derived cells for treatment of B-cell acute lymphoblastic leukemia
Pfizer - Phase I clinical trials ongoing as of 2018 for allogeneic CAR-T cell therapy UCART19
Sorrento Therapeutics - anti-CEA CAR-T in clinical trials with patients with carcinoembryonic antigen–positive (CEA+) cancers
Zencapsule - develops delivery systems for immune checkpoint inhibitors
Ziopharm - non-viral “Sleeping Beauty” (SB) platform for manufacturing of genetically modified CAR+ T cells
Agios Pharmaceuticals - Partnered with Celgene for a metabolic immune-oncology approach that involves altering the metabolic state of immune cells to enhance the immune response to cancer
PD-1 inhibitors include pembrolizumab and nivolumab.
PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab.
B cell depletion therapies (BCDTs) are used to prevent B cell lymphomas from reoccurring. The treatments are reagents such as anti-CD20, anti-CD19 and anti-BAFF antibodies that bind surface glycoproteins on B cells. BCDTs are also being developed to treat autoimmune diseases in which B cells are involved.
BCDT drugs in clinical trials for treatment of multiple sclerosis include the anti-CD20 and anti-CD19 drugs rituximab and ublituximab. Ocrelizumab and ofatumumab are anti-CD20 treatments approved for relapsing multiple sclerosis. Ocrelizumab, obinutuzumab, obexelimab, obexelimab and rituximab are anti-CD20 and anti-CD19 treatments in clinical trials for treatment of systemic lupus erythematosus.
The BAFF inhibitor, anti-BAFF, belimumab is approved for systemic lupus erythematosus. BAFF is a key survival factor on B cells. Belimumab blocks binding of BAFF to BAFF receptors on B cells. Several anti-BAFF treatments are in clinical trials for autoimmune diseases such as Sjogren syndrome, rheumatoid arthritis and neuromyelitis optica spectrum disorders (NMOSD).
Inhibiting Bruton tyrosine kinase (BTK), expressed in B cells and myeloid cells, is another strategy for removing B cells. Small molecule BTK inhibitors are in clinical trials for multiple sclerosis.
CAR-T cell therapy targeting anti-CD19 is in clinical trial stage for systemic lupus erythematosus. As an alternative to using an anti-CD20 antibody (Rituximab) for B cell depletion, CAR-T cell therapy in which CD8+ T cells express CD19-targeted chimeric antigen receptros (CARs) were used to deplete B cells expressing CD19. CAR-T cell therapy targeting anti-BCMA is in clinical trials for myasthenia gravis and multiple myeloma. Anti-desmoglein 3 is targeted by the CAR-T therapy in clinical trials for mucosal-dominant pemphigus vulgaris.
Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes that have immunosuppressive effects, and play an important for in the immune response to self-antigens and have a role in maintaining self-tolerance. Autoimmune diseases develop from a loss of self-tolerance and chronic immune responses against the body’s own cells, tissues and organs. Therapeutic strategies aim to induce or expand Tregs in order to increase the anti-inflammatory and tolerogenic activities of the immune system.
CAR-T Companies: The Meteoric Rise Of Cellular Immunotherapies
The Future of Immunotherapy: A 20-Year Perspective