Immunological Dreams at #ASCO14

Two things caught my attention: 1) The 5-year survival rate of all cancers has improved from 49% to 68% in the past two decades with more than 19 million cancer survivors expected by 2024 and the knowledge of how to manipulate the immune system against the dreaded disease. We will discuss the latter further.

The hallmark of scientific work seems to have been in the realm of Immunosurveillance and cancer. The thrust of the argument for better control of the malignant tragedy is based on the Adaptive Immunity against cancer.

The knowledge that there are lymphocytic infiltrates found within the cancer milieu is well known for decades. It was realized some 30 years ago in the colorectal cancer domain that those patients who had lymphocytic infiltrates in their cancers did better with stage, disease progression and overall survival. Now with the journey of these lymphocytic infiltrates laid out, actionable sites have become visible for the probing and assault against this deadly scourge.

The adaptive Immunity to be effective has to have two components of T-lymphocytes: The T Helper cells (Th1) and the Cytotoxic T-Cells (CTL). The CTL upon stimulation secrete TNF-α and Interferon-ϒ, both of which have limited immunity. The Regulatory cells are the T-regs that oppose the inflammatory signals via TGF-β and Interleukin to suppress the CTL from further activity in order to limit immune activity and tissue destruction. A balance therefore exists between the T-regs and the Th-cells.

The universal knowledge states that Immunity is based on the “Self” and the “Non-Self.” The T-Cells are programmed to recognize and destroy any foreign invaders. However as a means of checks and balances there is a proviso that allows for some self-control to prevent an all-out attack against the “self” should the invaders be contained. This mechanism is available via control-points also called appropriately “Check-Points.” 

The express function of modern-day immune manipulation against cancer is to unbalance the inhibitory signals to the checkpoints to allow for a full-throated attack against the wayward cancer cells. Meanwhile, not to be outdone, the cancer cells have tricks up their sleeves too and try to fool the Immune T-Cells with their vile secretory expressions of TGF- β and Interleukins along with other co-stimulatory cytokines like CD28, CD137 and OX40 to force the immune cells to lay down their arms in quietude. This fight is worth a few more words.

As the cancer cell invades tissues, it is also invaded by these immune cells. The Immune cells have to recognize the cancer cell surface antigens (Major HistoCompatibility Loci) and then” express their outrage” via their secretory products to limit growth of these invaders. Three mechanistic offenses are launched against the cancer cells:

Retaliation 1: The recruitment of the Th1 and CTLs to gear for a limited response. This is followed by an assessment of the damage against the enemy. If the immunity is weak this is the last signal and the cancer enjoys free reign without any further intervention. In this scenario, for example, therapeutic intervention with Herceptin and Chemotherapy are the mainstay of therapy in breast cancer.

Retaliation 2: In this format, the initial response is followed by ancillary assault via the co-stimulatory APCs and the Checkpoint regulations. PD-, PD-L1,PD-L2, which are “programmed cell death” inhibitors.   Inhibition of these checkpoints asserts limitations on the immune response and allows cancer cell growth. By inhibiting the inhibitors, the immune attack continues. The PD-, PD-L1,PD-L2 molecules fit the cell receptor sites on the CTLs and abrogate their ability to fight. Anti PD-1, PD-L1 and PD-L2 antibodies therefore allow a new breed of T-Cells to invade along with their co-stimulatory cytokines such as TNF- α and the Interleukins to play havoc with the inflammatory phenomenon and thus destroy the cancerous invaders. Checkpoint inhibitors and Monoclonal antibodies directed against the tumor cell expressed proteins are the mainstay in this approach. Disease such as Melanoma, Non-Small Cell Lung Cancer and Colorectal cancer has been successfully treated with this form of immune modulation.

Retaliation 3: Inactivation of the TGF-Beta and the Interleukins. The cancer cells co-opt the protein expression and inactivate the inflammatory signaling secretions. Again the Checkpoint inhibitors and Monoclonal Antibodies along with other conventional measures can be used with impunity against the cancer.

Would you agree that the knowledge of immune function activity in and around the cancer has meaningful repercussions in our battle against this disease? We have yet to determine the EMT (Epithelial Mesenchymal Transition) effect on Immune modulation and that may hold more answers in the future. Is that a concept worth exploring?

Checkpoints: Initial phase= CTLA-4 (Iplimumab-binds to APC via CD28), Secondary phase when cytokines have been released then PD-1(expressed by  T-cells, NK cells), PD-L1 (APCs and Epithelial cells), PD-L2 ligands inhibit CTL activity, (Melanoma, NSCLC, CRC) LAG-3

Antibodies against Checkpoints and in development: Iplimumab CTLA-4, Nivolumab PD-1, PD-L1(BMS-936559, PD-L2 (AMP-224, LAG3 (IMP321.

Speaking about MoAbs, Ibrutinib against the Bruton Tyrosine Kinase against CLL is a big story that we can discuss in the future.

References:

Scott N. Mueller, PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice J Clin Invest. 2010;120(7):2508–2515.

Shoba Amarnath The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells. Sci Transl Med 30 November 2011: Vol. 3, Issue 111, p. 111ra120

Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–245.

http://jedismedicine.blogspot.com/search?q=PD-1

Ahmed Tarhini, Earnest Lo, David, Minor.  Releasing the Brake on the Immune System: Ipilimumab in Melanoma and Other Tumors. Cancer Biother Radiopharm. Dec 2010; 25(6): 601–613. Article online: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011989/