Anti PD-1 and anti PD-L1 Immunotherapies

Summary:

A very new and promising immunotherapy approach to the treatment of cancer is the use of immune checkpoint inhibitors. These treatments work by “taking the brakes off” the immune system, so that the immune system becomes more effective in attack against cancer. Several different types of checkpoint inhibitors, targeting different checkpoints or “brakes” on immune cells, are currently in use. One of the most studied category of such check point inhibitors is the anti PD-1/anti PD-L1.

PD-1 inhibitors: 
Nivolumab (Opdivo®), made by Bristol-Myers Squibb (BMS), approved in 2015
– Pembrolizumab (Keytruda®), made by Merck, was approved in 2015
Pidilizumab (CT-011), made by Cure Tech and sold to Medivation, in clinical trials
AMP-224

PD-L1 inhibitors:
Atezolizumab (MPDL3280A), made by Genentech/Roche, in clinical trials
– Durvalumab (MEDI4736), a PD-L1 antibody, made by AstraZeneca/MedImmune, in clinical trials
– Avelumab (MSB0010718C), made by Merck KGaA and P, in clinical trials
– BMS-936559, made by Bristol-Myers Squibb, no longer under clinical development

The good aspect is that although the above inhibitors are very new and most in clinical trials (which can only be accessed by a few), Nivolumab and Pembrolizumab are approved and as a result are accessible to everyone. Indeed, they are expensive. It costs about 2000-3000 euro every 2-3 weeks, assuming the dose indicated by the clinical trials and depending on the weight of the patient. Specifically, 100mg vial Opdivo costs about 1800euro in Germany. However, there are clinics in Germany such as that of Prof Nessulhut, who are using lower doses (which would cost about 1000 euro/month) while combining PD-1 inhibitors with Dendritic Cell vaccines. Such combinations may be more effective and with less chances for side effects so that in the end the patient would end up paying about 5500 euro/month and getting both a PD1 and a DC vaccine and possibly for shorter time to response, since the effectiveness is claimed to be better.

Note that many private clinics in Germany are now using (off label) PD1 therapy, since it is widely available.

Results from clinical trials:

For the PD1/PDL1 inhibitors, based on what I read the statistics seems to look like this: 20% partial an complete results, 40% stable diseas, 40% no response. However, this is a statistics over all cancer types and depending on the cancer type the partial and complete response may be much higher such as for melanoma, bladder, RCC, etc.

Also the results seem to be much better if the tumor immune cells are positive for PD-L1. In that case the response may even go up to 80%. Ref

Results from some anti PDL1 inhibitors in various cancers: http://www.mycancergenome.org/content/drug-class/pd-l1-inhibition-and-inhibitors/

Here is a recent (April 2015) good review on all the above including clinical results http://www.nature.com/bjc/journal/v112/n9/full/bjc2015124a.html#tbl2

From Nessulhut’s clinic I heard of success rate >50%.

Side effects:

Toxicities associated with checkpoint inhibitor immunotherapy: http://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy?source=see_link
(Immune-mediated pneumonitis has been reported with pembrolizumab and nivolumab, but is rare, with an overall incidence of less than 3 percent in over 400 patients in the initial clinical experience with this agent)

This therapy can lead to many side effects, most grade 1 or 2. Examples of side effects are diarrhea, thyroid issues, pneumonia, etc. However, these auto immune reactions can be controlled in most cases with medication that suppresses immune system (e.g. Corticosteroids). If the auto immune side effects are continuing the therapy is stooped.

Optivo side effects: http://www.rxlist.com/opdivo-side-effects-drug-center.htm

How to manage toxicity of Immunotheraphies with CTLA4 and anti PD1: https://content.webges.com/precimmuno/public/download_uploaded_media/pdf/37

Synergy 

VEGF inhibitors and anti-PD1: Combination immunotherapy + VEGF targeted therapy is the optimal systemic strategy for metastatic RCC http://www.niu.edu/kca/chicago/docs/d4-plimack.pdf
Note: Thalidomide is a good VEGF inhibitor

Obatoclax (X15-070 , GX15): Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly downregulated FOXP3 and CTLA-4 in a dosedependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8+ :Treg and CD4+ :Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8+ T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitorhttp://www.jimmunol.org/content/early/2014/02/07/jimmunol.1301369.full.pdf

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor  microenvironment and enhance immunotherapy http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491458/pdf/pnas.201215397.pdf

Aspirin could hold the key to supercharged cancer immunotherapy http://medicalxpress.com/news/2015-09-aspirin-key-supercharged-cancer-immunotherapy.html  “Giving patients COX inhibitors like aspirin at the same time as immunotherapy could potentially make a huge difference to the benefit they get from treatment. It’s still early work but this could help make cancer immunotherapy even more effective, delivering life-changing results for patients.”

Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. http://www.ncbi.nlm.nih.gov/pubmed/21611872  CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells
T regulatory ( treg ) in tumors inhibit efficacy of immune checkpoint inhibitors  http://m.cancerres.aacrjournals.org/content/early/2015/07/24/0008-5472.CAN-15-1082.abstract

Plerixafor (CXCR4 inhibitor): Blocking the CXCR4/CXCL12 interaction, using the small molecule CXCR4 inhibitor AMD3100, leads to sensitivity to aPD-L1 (Ref.)

TLR agonists such as Imiquimod or Immunomax: Currently a clinical trial combining topical imiquimod and PD-1/PD-L1 blockade for treating breast cancer cutaneous metastasis is also being planned in the University of Washington. The idea behind this combination is based on the fact that TLR agonists such as imiquimod are believed to induce e.g. IL-10, Treg, and PD-L1. As a result, this combination would address the induced PD-L1 http://journal.frontiersin.org/article/10.3389/fimmu.2014.00083/full

Radiotherapy: Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? http://www.nature.com/nrclinonc/journal/vaop/ncurrent/full/nrclinonc.2016.30.html

ACAT1 inhibitors (such as Piperine, Honokiol, Omega3): https://www.cancertreatmentsresearch.com/cholesterol-cancer-acat-inhibition/

References:

PD1/PDL1: http://www.oncologieinperspectief.avl.nl/media/1465915/Sessie%201%20-%20II%20ochtend%20Immunotherapie%20presentatie%20Meervaart%20MVDH2%20Juni%202015.pdf

Anti-programmed cell death protein-1/ligand-1 therapy in different cancers http://www.nature.com/bjc/journal/v112/n9/full/bjc2015124a.html There is already evidence from at least one randomised trial that anti-PD-1 therapy is superior to chemotherapy in the treatment of patients with metastatic melanoma, and two anti-PD-1 antibodies, pembrolizumab and nivolumab, have been approved by the US Food and Drug Administration for the treatment of patients previously treated for metastatic melanoma. It is anticipated that approvals by drug regulatory bodies will be forthcoming in several cancers in the next months.

Neutrophils Regulate Humoral Autoimmunity by Restricting Interferon-γ Production via the Generation of Reactive Oxygen Specieshttp://www.ncbi.nlm.nih.gov/pubmed/26257170

 

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15 thoughts on “Anti PD-1 and anti PD-L1 Immunotherapies

    1. Hi Anna, that is a very good question and was wondering about that too. For some time it should be stable as I know at one clinic in Germany they were administrating less than one vial and asking the payment for exactly the mg used. You can check with the clinics in Germany. Maybe you can check these documents for the info:
      http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf
      http://packageinserts.bms.com/medguide/medguide_opdivo.pdf
      Actually now I realize that it comes as a solution in a vial. So it should be no issue using the quantity you need and teh rest store as recommended.

      1. In paper states clearly 24 hours but I think it is due to lack of preservatives. I just wonder if it is still bioligically active?
        Which clinic do you have in mind where I could ask?

        1. Please check again Anna. 24 hours is related to max storage time (at a temp between 2 and 8C) after it was mixed with saline:

          Preparation
           Withdraw the required volume of OPDIVO and transfer into an intravenous container.
           Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose
          Injection, USP, to prepare an infusion with a final concentration ranging from 1 mg/mL
          to 10 mg/mL.
           Mix diluted solution by gentle inversion. Do not shake.
           Discard partially used vials or empty vials of OPDIVO.
          Storage of Infusion
          The product does not contain a preservative.
          After preparation, store the OPDIVO infusion either:
           at room temperature for no more than 4 hours from the time of preparation. This
          includes room temperature storage of the infusion in the IV container and time for
          administration of the infusion or
           under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the time
          of infusion preparation.
          Do not freeze.

  1. Hello Daniel I am applying your recommendations of synergy for the PDL-1 therapy that is following my wife (Durvalumab + Monalizumab) I have not been able to achieve Plerixafor, but if interferon-gamma also favors this therapy.I have read various clinical trials in which the gamma interferon is used to know the dosage but I find that in each one is different.In is 1-5 ,15-20,29-34 and in others it is 8,10,15 and 17 days the dosage always50 mcg/m2.
    Some idea of the dosage most appropriate?.The therapy seems to be working help please

    than you

  2. Two strategies to improve checkpoint inhibitor therapies:

    Targeting β-adrenergic signaling ==> beta-blockers (e.g. Propranolol):
    http://cancerres.aacrjournals.org/content/early/2017/08/16/0008-5472.CAN-17-0546

    Targeting Myeloid supressor cells ==> H1-antihistamine (e.g. Desloratadine):
    https://immuno-oncologynews.com/2016/11/23/myeloid-cell-targeting-may-strengthen-immune-checkpoint-inhibitors-study-reports/
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056279/

  3. Hi Marco,
    the normal dosage for allergic purposes is 1 x 5mg per day but it is sometimes prescribed up to 4 x 5mg per day. It is generally well tolerated. It’s halflife is 27h

  4. I hear from TV some of these drugs have been approved in Romania, around the time of death of our King Mihai, coincidence or not.
    Sadly there is no more information available other than, they are given for free to people with insurance.
    Would any of them do anything for my mom? NSCLC.

  5. A possible synergy between Nivolumab and Electrochemotherapy, in a heavily pretreated metastatic melanoma patient. Quoting (from abstract):

    She showed a biphenotypical response to nivolumab; a mass on the anterior axilla was progressing while the other lymph nodes had regressed. Owing to the accessibility of the subcutaneous lesion with external electrodes, ECT was performed using IGEA Cliniprator device through a hexagonal electrode on the progressive mass, while on nivolumab treatment. A complete response was achieved, with no evidence of disease at 4 years since her local recurrence.

    Electrochemotherapy with anti-PD-1 treatment induced durable complete response in heavily pretreated metastatic melanoma patient. PMID: 29271783

  6. There seems to be a synergy between Galunisertib, a TGFβ inhibitor (also anti-fibrotic and decreases stem markers), and anti PD-L1 therapy, quoting:
    Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways.

    Targeting the TGFβ pathway with Galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade. PMID: 29866156 And Galunisertib seems to be well tolerated.

  7. Dear friends, Daniel.

    My mother is still alive, but that’s it. Most likely not for long.
    I wish to underline the fact that, while some people do get well with some treatment/s. Most of the time treatments only seem to worsen everything.
    Our hope makes us thirsty for more and more and more and more, becoming treatment dependent, and then more treatment to treat the treatment side effects that brings even more or new side effects.
    To treat, or not to treat…. that is the question.
    Our story is soon ending, as the chances favour that. I’ve done everything in my power to not let go.
    There’s no sufficient number of words to describe everything.
    Treatment, a fading illusion offering hope for the desperates.
    Check for the side effects, before making a decision!!!
    I have no regret for my choice of helping and forcing the doc, my mother’s wish was for imunotherapy (nivolumab – opdivo), i am proud i got her to try it, as she always wanted, after seeing Imunotherapy on tv news and then the nobel prize.
    Besides it was our last fda approved drug to be tried, the last stick, one final canon fire for my mom.
    I know i made the right choice, didn’t turn our well, it’s one of those 1% affected thing. When life sucks, expect more.
    Check for side effects!!! Wait, think, consult, decide, accept possibilities after choice.
    Don’t regret things, thinking this or that. You did what you felt was best, given the information you were able to obtain.
    Take your time and talk to specialists and no they are not specialists just because they wear a white coat and a name tag.

    Thank you for all the help. – And yes, i’ve been warned.
    Best wishes for everyone.
    Alex

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