Different Modes of Tumor Immunotherapy
1. Passive immunotherapy with monoclonal antibodies or antibody-like molecules
2. Adoptive cellular therapy with a... [Show More] ntitumor T cells
3. Immune checkpoint blockade-targeting T cell inhibitory pathways
4. Vaccination with tumor antigens
5. Various other approaches for stimulating antitumor immunity
Passive immunotherapy with Abs or antibody-like molecules
- Passive antibody therapy: rapid, very specific, without long-lived immunity
- Some anticancer mAbs have been used for>20 years, and many more are now approved or in advanced development
- Recombinant single polypeptide proteins with AB-like Ag-binding sites, termed single chain variable fragments, specific for tumor antigens have been developed for cancer treatment
Adoptive Cellular Therapy with Antitumor T cells
- This therapy is to transfer of immune cells that have antitumor reactivity into a tumor-bearing host. The immune cells are derived from a cancer patient's blood or solid tumor and then are treated in various ways in vitro to expand their numbers and enhance their antitumor activity, before reinfusion back into the patient
Adoptive Cellular Therapy with Antitumor T cells 2.1
- T cells specific for tumor antigens can be harvested from a patient's tumor tissue or blood, expanded and activated in vitro, and infused back into the cancer patients. This approach has some succuss in treating melanoma
- In-vitro: Stimulation of cells with tumor neoantigens and with anti-CD3, anti-CD28 and IL-2
- In-vitro: Transduction of patient's T cells to express TCRs specific for tumor Ag known to be displayed by HLA molecule - using lentiviral expression vector
Chimeric Antigen Receptor T cells Therapy (CAR T cell Therapy)
- Adoptive therapy using T cells expressing chimeric antigen receptors (CARs) has proved successful in some hematologic malignancies, and it is being developed for other tumors
- CARs are genetically engineered membrane-bound receptors with tumor antigen-specific binding sites encoded by recombinant Ig variable genes (i.e., single chain variable fragments) and cytoplasmic tails containing signaling domains of both the TCR complex and T cell costimulatory receptors
Chimeric Antigen Receptor (CAR)
- CAR is composed of an extracellular immunoglobulin single chain variable fragment specific for a tumor antigen, and cytoplasmic signaling domains that activate T cells, such as the {} chain immunoreceptor tyrosine-based activation motif (ITAMs) and motifs in the cytoplasmic tails of the costimulatory receptors CD28 and 4-1BB, which promote robust T cell activation
The CAR T Protocol
- Isolate T cells from peripheral blood of the cancer patient
- Infect with CAR-encoding retroviral or lentiviral vectors
- Stimulate with anti-CD3 and/or anti-CD28 antibodies to expand their numbers
- Transfer (infuse) the expanded CAR-expressing T cells back into patient. (Prior to transfer, the patients are usually treated with drugs that deplete their own lymphocytes, which maximizes the proliferation of transferred CAR-T cells)
- The transferred T cells undergo robust expansion and activation in the patient, in response to tumor antigen recognition by the Ig domain of the CAR and costimulatory signal provided by the signaling domains
- CAR T cell-mediated tumor cell killing: Direct cytotoxicity; Cytokine-mediated mechanisms
CAR T cell Therapy
- CD19-specific CAR-T cells: For treatment of various B cell malignancies that are refractory to other treatments, including chronic lymphocytic leukemia, acute lymphoblastic leukemia, and B cell lymphomas
- CD20-specific CAR-T cells: For B cell lymphomas
- Memory CAR-T cells may persist in the treated patient, and the immune surveillance against tumor recurrence is maintained
CAR T cell Therapy Unwanted/Adverse Effects
- CARs specific for CD19: Also kill normal B cells, but not Ab-producing plasma cells (the latter cells do not express CD19)
- Cytokine Release Syndrome: Due to intense systemic inflammatory response; Can be managed by administrating anti-IL-6R Abs, Can be decreased by cytotoxic chemotherapy to reduce tumor burden before CAR T cell transfer
- Serious Neurotoxicity: Die to the secreted cytokines get into the brain - causing long-term CNS damage, especially in children
- The emergence of antigen-loss tumor variants. This problem can be reduced by simultaneously expressing CARs specific for two or more tumor antigens
- In some patients, transferred CAR-T cells appear to become unresponsive over time, and initially controlled tumors have recurred
- Treating solid non-hematologic tumors with CAR-T cells has been unsuccessful
Costimulation
- The lack of B7 expression in the absence of innate immunity may help to limit inappropriate adaptive immune response
- When a T cell receive both signal 1 and signal 2, the T cell is activated, IL-2 is expressed, and clonal expansion of Th cells specific to that foreign epitope occurs
- Activated T cells eventually down-regulate CD28 expression and up-regulate CTLA-4 expression. CTLA-4 binds B7-1 and B7-2 with much higher affinity than CD28. Interaction of CTLA-4 with B7-1 or B7-2 inhibits T cell proliferation. This is a physiologic mechanism for self-limitation of the immune response (checkpoint signal)
Immune Checkpoint Blockade: Targeting T cell inhibitory pathways
- Immune Checkpoint: A mechanism of immune cell inhibition that restrains activation
- Immune checkpoint signals: CTLA-4, PD-1, Several others (LAG3, TIM3, etc.)
- Blockade of T cell checkpoint/inhibitory molecules has emerged as one of the most promising methods for effectively enhancing patients' immune responses to their tumors
CTLA-4: Its role and function
- CTLA-4 is a member of the Ig superfamily, expressed by activated T cells and transmits an inhibitory signal to T cells
- CTLA-4 is homologous to the T-cell co-stimulator CD28, and both CTLA-4 and CD28 bind to B7-2 (CD80) and B7-2 (CD86), on antigen -presenting cells (APCs)
- CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands
- CTLA-4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. CTLA-4 is also found in Trefs (regulatory T cells) and contributes to their inhibitory function
- T cell activation through the TCR and CD28 leads to increased expression of CTLA-4
- Activated T cells down-regulate CD28 expression and up-regulate CTLA-4 expression
- CTLA-4 binds B7-1 and B7-2 with much higher affinity than CD28
- Interaction of CTLA-4 with B7-1 or B7-2 inhibits T cell activation and proliferation. This is a physiologic mechanism for self-limitation of the immune response
- Because CTLA-4 limits the initial costimulation dependent activation of T cells in secondary lymphoid organs, mutation or blocking this receptor leads to severely dysregulated immune responses with enlarged lymph nodes, lymphoproliferation and multiorgan inflammation [Show Less]
