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Immunotherapy and RET Lung Cancer

By July 8, 2024July 10th, 2024No Comments

Immunotherapy is a type of treatment that uses the body’s own immune system to fight cancer. Cancer cells start from healthy normal cells that become abnormal, and sometimes the immune system does not recognize abnormal cells as foreign, making it difficult to target them. Immunotherapy helps to stimulate the immune system to better recognize and attack cancer cells.

The immune system defends the body against infections. It can identify and attack different pathogens that the body does not recognize as its own like bacteria, viruses, or fungi, and it is also able to identify and attack cancer cells.

Immune Checkpoint Inhibitors: Taking Off the Immune System ‘Brakes’ for Cancer Treatment

There are several types of immunotherapies that have been developed to treat cancer including the immune checkpoint inhibitors (or immune checkpoint blockade) such as anti-PD-1/PD-L1 or anti-CTLA4. These were approved for the treatment of non-small cell lung cancer (NSCLC) alone or in combination with chemotherapy (ipilimumab, nivolumab, pembrolizumab, durvalumab, atezolizumab, and cemiplimab) (1). These drugs fight cancer by taking off the ‘brakes’ of immune cells, allowing them to effectively attack and destroy cancer cells.

In 2018, the Nobel Prize in Physiology or Medicine was awarded to Drs. James Allison and Tasuku Honjo for their work on the CTLA-4 molecule and the development of the first-in-class antibody that could bind to CTLA-4 and block its function (Ipilimumab) (2).

Checkpoint blockade inhibitors have shown great and durable responses in NSCLC patients, especially in patients who presented high levels of PD-L1 expression and/or high number of mutations (called tumor mutation burden (TMB) in their tumors. These drugs have revolutionized the treatment of NSCLC, but they do not always work for every NSCLC patient. Researchers are studying the factors that determine which patients are more likely to respond to immune checkpoint blockade treatment and which patients are less likely to respond. Hopefully, with additional research, immunotherapy will become a more reliable way to treat cancer.

Immune Checkpoint Blockade Immunotherapy for RET NSCLC

Several studies and clinical trials have established the efficacy of immune checkpoint blockade therapies in NSCLC patients. Despite this, studies have shown that immune system checkpoint inhibitors alone have low efficacy to fight cancer in the treatment of patients with NSCLC with oncogenic-driven tumors such as EGFR, ALK, ROS1, or RET (3-5).

For RET NSCLC, one explanation of this low efficacy may be that RET lung cancers are characterized by having low levels of PD-L1 expression and low TMB in the majority of patients (3). Because of this, other therapeutic strategies such as RET targeted therapy should be considered before administering immunotherapy alone for the treatment of patients with RET alterations.

Other Immunotherapies

Besides immune checkpoint blockade immunotherapy, there are other types of immunotherapy treatments that use different strategies to enhance immune system response to better recognize and kill cancer cells.

1. Adoptive Cellular Therapies (ACT)

ACT is another class of cancer immunotherapy based on the isolation of the immune T cells that can recognize tumors, their expansion in the lab, and the re-infusion of the selected immune T cells back into cancer patients. There are several different types of ACTs:

Chimeric antigen receptor (CAR) T-cell therapy

In CAR T-cell therapy, the immune T-cells are taken from a patient’s blood and re-engineered in the lab to express a receptor called Chimeric Antigen Receptor (CAR) that specifically binds to a surface protein that is present in the cancer cells. These CAR T-cells are expanded in the laboratory and infused back to the patient. CAR T-cell therapy has been successful in treating some blood cancers like leukemias or lymphomas, and it is being studied in clinical trials for the treatment of solid tumors.

Tumor-infiltrating lymphocytes (TIL) therapy

TIL therapy uses the T cells that are found in patient’s tumors, which are called tumor-infiltrating lymphocytes or TILs. These TILs are analyzed to identify the ones which recognize and attack the tumor cells. When the best TILs are selected, they are expanded and infused back to patients. TIL therapies rely on patient’s tumor biopsies as the biopsies as the TILs are isolated from the tumor biopsies. TIL therapy has proven efficacious in patients with melanoma and other solid tumors (6) and is under investigation for the treatment of NSCLC patients (7).

T-cell receptor (TCR) therapy

In contrast to CAR T-cell therapy, which uses T cells that recognize a specific protein expressed on the surface of a tumor cell, TCR T-cell therapy utilizes T cells that can recognize any protein expressed on tumors (intracellular or surface proteins). TCR T-cell therapy utilizes the immune T cells from a patient’s blood that are re-engineered in the lab to express a specific TCR that binds to proteins expressed in the cancer cells. This therapy has been proven effective in some cancers expressing including KRAS mutant cancers (8).

  • TCR therapies for RET cancers: Dr. Alexandre Reuben, a Happy Lungs Project-funded researcher, is currently investigating the development of novel TCR T-cell therapies for RET cancers. His team is testing some newly identified RET antigens (part of the RET protein that is able to induce an immune response) that are able to drive a T-cell response and are great candidates for the development of new adoptive TCR therapy for RET tumors. More information can be found in our 2023 RET cancer research update.

2. Therapeutic Cancer Vaccines

Therapeutic cancer vaccines expose your immune system to cancer antigens so it can react and destroy cancer cells. The main goal of cancer vaccines is to produce tumor regression, eradicate any residual disease, and establish lasting anti-tumor memory. There are several types of vaccines depending on the compound being introduced: mRNA or DNA, peptides (part of a protein), immune dendritic cells (DCs)), etc. The COVID-19 pandemic opened the door for testing mRNA vaccines as cancer treatments for some solid tumors. mRNA vaccines are also under investigation in clinical trials for the treatment of NSCLC (9, 10).

3. Monoclonal Antibody Treatment

Monoclonal antibodies are components of the immune system that can recognize and bind antigens, triggering the immune system to destroy them directly or to help other immune cells to destroy the antigen. Monoclonal antibodies recognize one particular antigen.

Antibody-Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) are antibodies that are equipped with anti-cancer drugs (usually cytotoxic agents that kills tumor cells), so when the antibody binds to cancer cells it also delivers the cytotoxic agent that can destroy the cancer cells. Trastuzumab deruxtecan was the first ADC approved for HER2-mutant NSCLC. Several ADCs are currently under investigation for NSCLC (11).

Bispecific Antibodies

Bispecific antibodies are a type of antibodies that can bind to two different antigens at the same time. Some bispecific antibodies can bind to two antigens that are present on tumor cells and other can target an antigen present on cancer cells and immune T cells, so they bring the cancer cell and the immune cell into close proximity (12).

Bispecific Antibodies for RET cancers

Some of the RET cancer patients who become resistant to RET inhibitors present increased expression of the epidermal growth factor receptor (EGFR) or mesenchymal-epithelial transition (cMet). These molecules can bypass the RET inhibition and activate alternative cancer cell signaling pathways that allow these cancer cells to grow. Amivantamab is a bispecific antibody that binds to EGFR and MET that is being investigated in a phase 1/2 trial in RET NSCLC patients who progressed on RET inhibitors. The new clinical trial is led by Dr. Tejas Patil from University of Colorado. More information about the trial here.

References and Resources

  1. Olivares-Hernández A et al. Immune checkpoint inhibitors in non-small cell lung cancer: from current perspectives to future treatments-a systematic review. Ann Transl Med. 2023;11(10):354. doi:10.21037/atm-22-4218
  2. Wolchok J. Putting the Immunologic Brakes on Cancer. Cell. 2018;175(6):1452-1454. doi:10.1016/j.cell.2018.11.006
  3. Offin M et al. Immunophenotype and Response to Immunotherapy of RET-Rearranged Lung Cancers. JCO Precis Oncol. 2019;3:PO.18.00386. doi:10.1200/PO.18.00386
  4. Mazieres J et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328. doi:10.1093/annonc/mdz167
  5. Negrao MV et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer. 2021;9(8):e002891. doi:10.1136/jitc-2021-002891.
  6. Schoenfeld AJ et al. Lifileucel, an Autologous Tumor-infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non-small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors. Cancer Discov. Published online April 2, 2024. doi:10.1158/2159-8290.CD-23-1334
  7. Creelan BC et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021;27(8):1410-1418. doi:10.1038/s41591-021-01462-y
  8. Lu D, Chen Y et al. KRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors. Nat Commun. 2023;14(1):6389. Published 2023 Oct 12. doi:10.1038/s41467-023-42010-1
  9. Kiousi E et al. Progress and Challenges of Messenger RNA Vaccines in the Therapeutics of NSCLC. Cancers (Basel). 2023;15(23):5589. Published 2023 Nov 26. doi:10.3390/cancers15235589
  10. Bala Başak Öven et al., Abstract CT051: Preliminary results from LuCa-MERIT-1, a first-in-human Phase I trial evaluating the fixed antigen mRNA vaccine BNT116 + docetaxel in patients with advanced non-small cell lung cancer. Cancer Res 1 April 2024; 84 (7_Supplement): CT051
  11. Coleman N, et al. Antibody-drug conjugates in lung cancer: dawn of a new era?. NPJ Precis Oncol. 2023;7(1):5. Published 2023 Jan 11. doi:10.1038/s41698-022-00338-9
  12. Khosla AA, et al. Bispecific Antibodies in Lung Cancer: A State-of-the-Art Review. Pharmaceuticals (Basel). 2023;16(10):1461. Published 2023 Oct 14. doi:10.3390/ph16101461

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