Cancer Immunotherapy II

Definitions:
- Tumor-specific monoclonal antibodies (mAbs): Antibodies designed to target specific antigens expressed by tumor cells.
- Cytokines: Signaling molecules that mediate and regulate immunity, inflammation, and hematopoiesis.
- Adoptive Cell Transfer: A therapy that uses T cells or other cells from the patient’s immune system to fight cancer.
- Types of Immunotherapy:
- Passive Immunotherapy: Involves the direct administration of exogenous antibodies, such as monoclonal antibodies.
- Active Immunotherapy: Involves stimulating the patient's own immune system to attack cancer cells.

Immune Checkpoint Inhibitors: Designed to block proteins that suppress the immune response against tumors.
Oncolytic Viruses: Genetically modified viruses targeting and killing cancer cells.
Dendritic Cell Therapy: Utilizes dendritic cells to present antigens and stimulate T cell responses.

Definition: Immune checkpoints are inhibitory pathways crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological T cell responses.
Significant checkpoints:
- CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4): Regulates T cell activation.
- PD-1 (Programmed Cell Death Protein 1): Inhibitory receptor found on exhausted T cells.
- PD-L1 (Programmed Death-Ligand 1): Ligand for PD-1, often upregulated in tumors for immune evasion.
Mechanism: Tumor-infiltrating T cells often express PD-1 and CTLA-4, leading to an exhausted phenotype which can be countered by checkpoint inhibitors.
Examples of Checkpoint Inhibitors:
- Anti-CTLA-4 (Ipilimumab)
- Anti-PD-1 (Nivolumab, Pembrolizumab)
- Anti-PD-L1 (Atezolizumab, Durvalumab)

Efficacy Issues: Only 15-20% of patients respond to these therapies, with variations in tumor types affecting response rates.
Adverse Events: Immune-related adverse events can lead to discontinuation due to severe side effects (e.g. myocarditis).
Expression Variability: Not all tumors express high levels of PD-L1, impacting the likelihood of response.
Resistance Mechanisms: Tumors can adapt over time to evade checkpoint blockade, leading to unresponsiveness.

Focus Areas:
- Identification of predictive biomarkers for therapy efficacy.
- Investigation into tumor resistance mechanisms.
- Combination therapies with other drugs to enhance efficacy.
- Design of novel checkpoint inhibitors targeting additional pathways.

Relatlimab:
- Targets LAG-3 (Lymphocyte Activation Gene-3), expressed on T cells that inhibit activation and proliferation when bound to MHC Class II.
- Approved in 2022 combined with Nivolumab for melanoma treatment.
- Side effects noted were less severe in this combination compared to other combinations like Ipilimumab/Nivolumab.
Anti-TIM-3 Antibodies:
- TIM-3 (T cell immunoglobulin and mucin domain-containing-3): Another inhibitory receptor, binding to Galectin-9 and leading to T cell suppression.
- Example: INCAGN02390, a novel anti-TIM-3 monoclonal antibody showing promising results in Phase I trials.
Anti-TIGIT Antibodies:
- TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domain): Inhibitory receptor competing with co-stimulatory receptor CD226 for binding on DCs and tumor cells.
- Example: Domvanalimab, a novel anti-TIGIT monoclonal antibody in clinical trials for gastrointestinal and lung cancer.

Role: DCs are pivotal in linking innate and adaptive immunity, activating T cells through antigen presentation.
History:
- Discovered by Prof Steinmann in the 1970s; his personal battle with cancer led to pioneering work in DC therapy, culminating in the development of Sipuleucel-T (Provenge®
  ) for hormone-refractory prostate cancer.
Procedure: Isolation of monocytes from patients, incubation with recombinant proteins, reintroduction of ‘pulsed’ DCs to boost specific T cell activation.

Limited Efficacy: Therapy may not be effective in all patients.
Technical Complexity: Labor-intensive procedure requiring patient-specific cell harvesting and expansion.
Cost: High treatment costs (up to $100,000$ per patient for prostate cancer).

Definition: Genetically modified viral strains that selectively infect and lyse tumor cells while activating immune responses through the release of tumor antigens.
Example: Talimogene Laherparepvec (T-VEC), the first FDA-approved oncolytic virus therapy for melanoma (2015).
- Based on modified herpes simplex virus-1 with deleted virulence genes allowing selective replication in tumor cells and improved APC recruitment.

Ongoing Research: Focus on improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy to harness immune responses more effectively.