How to make anti-PD1 work better with a new player...LAG-3????

Our immune system is a wonder of cell function with checks and balances.  Cells can be turned on to help fight germs and tumors and other yuck we encounter, but can also be turned off so we don't suffer from the body attacking or hurting itself through too much of an inflammatory process (as it does in autoimmune diseases like lupus, arthritis and even asthma).  Here are some terms that might help in understanding the presentation and article below as it relates to how anti-PD1 works, why it might not, and what might be done to make it work better for folks when their cancer/melanoma rears its ugly head again.

Definitions:
YOU HAVE:
1. T-cells - a type of lymphocyte (white cell) with a "T-cell receptor" on the surface.  There are several types of T-cells.
     i)  CD4-T cells - (T helper cells)- express the CD4 protein on their surface and become activated when  exposed to peptide antigen, which is expressed on the surface of an antigen-presenting cell (like bacteria and tumor cells).  When active they increase in number and secrete cytokines that regulate/trigger the immune response to attack the invader.
     ii)  CD8-T cells - (cytotoxic T cells)- express CD8 on their surface and can destroy virus cells, tumor cells, and are implicated in transplant rejection.  They can be "inactivated" so that autoimmune diseases are prevented or decreased. (Many meds to decrease transplant rejection as well as the signs and symptoms of rheumatoid arthritis, ankylosing, and other autoimmune diseases work to do this.)
     iii)  Memory T cells - persist after an infection or vaccine to create immunity.
     iv)  T reg cells - (suppressor T cells)- these cells shut down T cell mediated immunity at the end of an immune reaction.  There are 2 types of the these CD4T reg cells:  Naturally occurring cells that begin in the thymus gland (CD4, CD25, and FoxP3 T regs) and Adaptive T regs that originate during a normal immune response.
     v)  Natural Killer T cells - These T cells recognize a different molecule from other T-cells.  (Instead of peptide antigens, they recognize a glycolipid antigen.)  When active, they can eliminate some tumor and invasive viral cells.

2.  PD1 - also called programmed cell death protein 1, is a membrane protein and a member of the extended CD28/CTLA-4 family of T cell regulators.  PD1 is expressed on the surface of activated T cells, B cells and macrophages (white cells that can be involved in tissue repair or engulf/digest debris or pathogens). Compared to CTLA-4, PD-1 is keyed to specific tissues with the PD-L1 ligand, while CTLA-4 is less specific.

3.  CTLA-4 - another T cell regulator, also called Cytotoxic T-lymphocyte Antigen 4, is a protein receptor that down regulates (can "turn off") the immune system.  It is found on the surface of T-cells.

4.  LAG-3 - a molecule on T reg cells that contributes to their suppressor activity.

MEDICINE:
5.  Anti-PD1 - Nivolumab by BMS and Pembrolizumab (MK-3475) by Merck - are monoclonal anti-bodies that block the switch on T cells so that PDL1, produced by tumor cells, can NOT bind with them and turn them off.

6. Anti-CTLA-4 - Ipilimumab/Yervoy - a monoclonal antibody created by BMS that works to activate the immune system by targeting CTLA4, a protein receptor that down-regulates the immune system in melanoma patients, thereby turning ON the T cells.

FROM TUMORS:
7.  PDL1 - a ligand produced by the surface of melanoma tumors that can bind to infiltrating T-cells and turn them off.

Attached here is a presentation by Charles Drake MD, PhD from John Hopkins, from the Perspectives in Melanoma XVII meeting in Baltimore in September 2013, where he gave a review of PD1 biology, and how anti-PD1 works, as well as factors that might make it more effective:
The Basic Biology of PD1 and thoughts about LAG-3

Primary points:  
Anti-PD1 (a PD1 blockade) causes -
    1.  An increased number of CD8 T-cells
    2.  Increased function of those CD8 T-cells
LAG-3:
Alone, anti-LAG-3 is not very effective.  However, when anti-PD1 is combined with a LAG-3 blockade, the effectiveness of the CD8 T-cells is even greater than when either is used alone.  Unfortunately, there was a high death rate in the mice given both.  However, that particular mouse population was genetically engineered to have NO LAG-3, not a normal circumstance.
When does Anti-PD1 work?  In the priming or the effector phase????
This remains somewhat unclear...or perhaps there is action in both phases.  In this data, it seems that when anti-PD1 is on board with the initial antigen exposure....it leads to not only increased discrete numbers of CD8 T-cells, but even greater T-cell function per individual cell.  Therefore, it may be that earlier treatment (prior to advanced disease) is more effective because more T-cells with greater function may be produced.  Additionally, in advanced disease, the addition of anti-LAG-3 (to anti-PD1) seems likely to create more effect.

We already have data indicating that patients who are taking anti-PD1 (MK-3475 for this data set) and are ipi naive have about a 40% response rate while patients who are ipi refractory have a lesser response (28%).  data as discussed by Ribas and Weber
We also know that data shows that with smaller tumor size, there is increased overall survival in melanoma patients treated with anti-PD1. Baseline tumor size as an independent prognostic factor
(Now, on that point, you have to bear in mind that no matter how active ones white cells may be, they can be overwhelmed...with infection (in cases of sepsis)...or with cancer cells....BUT....)
Both these issues may be addressed in a continuation of the ideas presented in the lecture...studied  specifically here:


Restoring Immune Function of Tumor-Specific CD4+ T Cells During Recurrence of Melanoma
Goding, Wilson, Xie, et al.  The Journal of Immunology, March, 2013.
   "Recurrent solid malignancies are often refractory to standard therapies....adoptive T cell transfer may benefit select individuals, the majority succumb to their disease.  ...developed a mouse melanoma model in which initial regression of advanced disease was followed by tumor recurrence.  During recurrence, Foxp3 tumor-specific CD4 T cells became PD-1+ and represented more than 60% of the tumor-specific CD4 T cells in the host.  Concomitantly, tumor-specific CD4 T effector cells showed traits of chronic exhaustion, as evidenced by their high expression of the PD-1...and LAG-3 inhibitory molecules.  Although blockade of the PD-1/PD-L1 pathway with anti-PD-L1 antibody or depletion of tumor-specific regulatory T cells (Tregs) alone failed to reverse tumor recurrence, the combination of PD-L1 blockade with tumor-specific Treg depletion effectively mediated disease regression.  Furthermore, blockade with a combination of anti-PD-L1 and anti-LAG-3 antibodies overcame the requirement to deplete tumor-specific Tregs.  In contrast, successful treatment of primary melanoma with adoptive cell therapy required only Treg depletion or antibody therapy, underscoring the differences in the characteristics of treatment between primary and relapsing cancer."

Primary points:
    Initially, blocking just PD-1 with anti-PD1 drugs will allow T cells to kill melanoma cells.  When relapse occurs, the immune response has been further suppressed by CD4 suppressor cells (T regs).  In relapse, reducing the number of T regs (Remember! These are the T cells that shut down the immune response!!) through drugs like cyclophosphamide or radiation...as is done before TIL therapy...plus the combination of anti-PD-L1 OR using anti-PD1 combined with anti-LAG3....showed the restoration of effective tumor killing by T cells.

So....all of this seems a good way of thinking about how to GET THOSE T CELLS FIRED UP!!!!  Initially AND in later stages of cancer progression.  I hope I was able to make it somewhat comprehensible.  Keep it up, you smart and enthusiastic research guys.  And you ratties....both the 4 and 2 legged sorts....hang tough!!!
Love - c