PD-1 and CANCER

We are the human race, the quintessence of dust, and the paragon of all life. We build bridges, roadways, industries and castles. Some of the castles we build are fortified with steel, mortar and bricks, while others are more in the mind. We build the ones in our minds with reason. This reason is based on an interplay between known and imagined, hypothesis and evidence, now and then, emotion and cognition. In these castles we house all our plans for the future. Barring the wrongly placed beams and windowsills that open into other facades without a hint of any landscape, where we can get crushed under or trip over and never come face to face with ourselves, here in this nebulous world, we are also vulnerable to high praise and effusiveness.

The first salvo against the Immune Checkpoint pathway was directed against the CTCL-4 cells in Malignant Melanoma with a drug called Yervoy (ipilimumab). This resulted in spectacular results in metastatic melanomas unseen previously with other concoctions of chemotherapy, hormones and Cytokines. That was and is worthy of praise. This is a follow through to that story. 

Imagine then my delight upon hearing about this new glint of miracles called the PD-1 and PD-L1.  New and novel targets to arrest, handcuff and incarcerate the ugly beast called cancer. Now here is a castle worth building.

So what are PD-1 and PD-L1:

Programmed cell death 1 ligand 1

Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production. PD-1, which stands for Programmed Death 1, is another compound in the CTLA4 family.  

Flowcytometric data

PD-1 is, for all practical purposes a “programmed cell death” receptor present on the Immune cell, a T helper (CD8) lymphocyte.  Okay, so why does this get my brain to sing?

Because...

Back in the yesteryears when sophistication was just a word and it implied what a woman wore to a party and how she behaved, today it has many different meanings. The ongoing rhetoric then was that certain cancers seem to follow a surprisingly different mode of action. For instance, Malignant Melanoma a deadly skin cancer would present itself, be cut out of its habitat on the human skin and then many years later it would surprise everyone especially the patient with a recurrence in a different organ. A similar scenario played out with Renal Cell carcinoma or Kidney cancer. The surgeon would take the kidney out and all would be well, until it wasn’t. 

Immune surveillance by T helper type 1 (TH1) cells is (not only) critical for the host response to tumors and infection…

Something did not sit well with the specialty of then, modern oncology. They suspected it had  to do with immunity and with little in their arsenal, threw everything available at it ~to subjugate it. In both of these above mentioned illnesses a concoction of Interferon and IL2 (Interleukin-2) were used. These are cytokines derived naturally (mass produced in the labs later) from a human host in response to a viral infection. Well in a small percentage of patients (less than 14%) it worked, but no one could put their finger on the "why".

Cell-mediated immune responses are initiated by T lymphocytes that are themselves stimulated by cognate peptides bound to MHC molecules on antigen-presenting cells (APC). T-cell activation is generally self-limited as activated T cells express receptors such as PD-1 (also known as PDCD-1) that mediate inhibitory signals from the APC. PD-1 can bind two different but related ligands, PDL-1 and PDL-2. PDL-1 is a B7-related protein that inhibits cell-mediated immune responses by reducing the secretion of IL-2 and IL-10 from memory T cells. This suggests that PDL-1 may be useful in reducing allogenic CD4+ memory T-cell responses to endothelial cells, thereby reducing the likelihood of host immune responses to allografts. At least two isoforms of PDL-1 are known to exist; this antibody is specific to the larger isoform. PDL-1 antibody has no cross-reactivity to PDL-2.

Immunohistochemistry of PD-1

Anyway not to belabor that issue, early this summer the scientists came up with antibodies to the PD-1 receptor and its Ligand (a mirror image that fits like a puzzle piece onto the PD-1 called PD-L1 or (“programmed cell death Ligand”) Interesting as it might seem that some cancer cells carry this Ligand protein on their surface (like bees to honey); A most surreptitious mechanism to evade immunity employed by the cancer cells. An ingenious self-protective act, this, most interesting of unities shuts down the immune pathway for surveillance against infection and cancer.

Immunofluorescent Flowcytometry

The programmed death-1 (PD-1) pathway has emerged as an important tumor-evasion mechanism. The two principal components of the PD-1 pathway are PD-1, an inhibitory receptor expressed on the surface of activated T cells, and programmed death ligand-1 (PDL-1), which is expressed on cancer cells. When PD-1 and PDL-1 join together, the T cell’s ability to target the tumor cell is disarmed. Thus, targeting either PD-1 or PDL-1 can stimulate the immune system and enhance T cells’ ability to lyse tumor cells.

Cellular proliferation model via PD-1 pathway

Using mice as models to establish the link between immunity and recovery from infection, the PD-1/PD-L1 complex so used, resulted in florid infections and the clearing of the infectious organism from the body was markedly delayed, hence the infectious organism grew within the mouse at a rapid rate. And if cancer was introduced into this mouse model, it also grew at a fairly vicious unchecked rate. This implied and with good reason that the cancer cell growth as well as the infectious organism was uninhibited by the “lack of” immunity in the mouse when the complex was added. This implication has been previously confirmed and ratified from several differing sources, indicated strongly that immunity puts the cuffs on cancer growth and infection, until it, the immunity, gets overwhelmed or side-stepped via deviant mechanisms. But here came the reasoning also why the cancer cell was able to escape this prison cell of body’s manifest resources. An analogy would be; the cancer cell surreptitiously using a clever tool/key was able to lock the room where the guards slept and continue to ravage the house.

Immuno-blockade of the PD-1

To everyone’s delight, came this news of an Anti PD-1 antibody (created in the lab) that is directed specifically against the Immune cell’s PD-1 surface protein that prevents the immune surveillance from being restrained. The data from recent studies proved that if one was able to unlock the door to the guard room, the guards would defend the fort. And they did! Lacking that as if adding the PD-1 antibody, things went awry. Patients who participated in the BMS-936558 (the PD-1 antibody) study and were given the PD-1 antibody (to unblock the T(helper) cells) had longer survivals and durable responses compared to those who did not receive this magic bullet. Voila, here was the clinical translational evidence of a scientific hypothesis. We still however, had to deal with the beams and the windowsills though.

Cancer cells and the T-Cell/APC interaction

There were a total pf 296 patients accrued in the study. Objective responses, as measured by standard RECIST criteria, were observed in patients treated with BMS-936558 across dose cohorts and across the NSCLC (6% to 32%), metastatic melanoma (19% to 41%) and RCC (6% to 32%) tumor types. Most responses were durable with response durations = 1 year in 65% of responders with = 1 year follow-up. The most common side effects were fatigue (24%) rash, (12%) and diarrhea, (11%). A First in human Phase I trial of the BMS-936559 against PDL-1 has shown durable responses with increased disease stabilization in heavily pretreated patients.

Infectious virus and the Immune mechanism of action

However there were two deaths that were directly related to the use of this PD-1 antibody. Both the deaths were due to florid pneumonia. That may seem unreasonable at first blush but looking at the mechanism of action, it becomes obvious.

Studies have demonstrated that PD-L1 on APCs (antigen presenting cells) can control peripheral tolerance and anergy Interestingly, PD-L1 expression on tissue parenchyma can protect against autoimmune pathology in diabetes models. The PD-1/PD-L1 pathway plays an important role in influencing T cell dysfunction and viral clearance during chronic viral infection.

Interrupting the immune surveillance will prevent the normal human host defense against an infectious bacterial agents and parasites as well. And that is exactly what also happened.

In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.

The difference between the anti PD-1 antibody therapy was that there were delayed cases of Autoimmune disease. This implied that blocking the PD-1 leads to an “overjazzed” immune surveillance later, that targets normal body cells downstream, whereas the anti PDL-1 antibody restricts immediate protection against the infectious organisms. We are learning where the badly placed beams and the windowsills are. We need  more experimentation to find the rest of these misplaced architectural anomalies.

PD-1 and PDL-1 antagonists in Production and Trials

The obvious question that lurks in the mind is, what is the future for this Anti PDL-1 and anti PD-1 antibody? The answer is simple; it is another piece to the anti-cancer puzzle. We can still one disease at the risk of inciting another one. Since the interlocking mechanisms of the body's modus operandi are fitted so cleverly by nature, harnessing one and not the other or the other can and does have unintended consequences. Having said that, the unintended consequences are hazards, once known become identifiable risks that can be mitigated. So moderate speed ahead as we carefully untangle the vines across the many paths that lead to this dreaded disease.

How substance, action and mode unite,

Fused, so to speak, together in such wise

That this I tell is one simple light. ~ Dante from The Divine Comedy

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.

Butler NS, et al.Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol. 2011 Dec 11;13(2):188-95.

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

LaGier J and Pober JS. Immune accessory functions of human endothelial cells are modulated by overexpression of B7-H1 (PDL1). Hum. Immunol. 2006; 67:568-78.

http://chicago2012.asco.org/ASCODailyNews/CRA2509.aspx

Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol. 2005;6(3):280–286.

Tsushima F, et al. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood. 2007;110(1):180–185.

Keir ME, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–895.

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.

Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–687.