Friday, February 3, 2017

Will checkpoint inhibitors cure cancer?


Will checkpoint inhibitors cure cancer?



Checkpoint inhibitors such as pembrolizumab, nivolumab and ipilimumab have generated tremendous excitement in the field of oncology. Although there are many older tumor immunotherapy approaches that also work and have resulted in product approval, none of them have resulted in a similar level of enthusiasm. There are several reasons for this. Checkpoint inhibitors are conventional drug molecules in the sense that they are monoclonal antibodies, a class of drugs widely used in the past two decades. Also, their use fits well into routine oncology practice; nurses can administer them intravenously every 2-3 weeks. Also, in contrast to cancer vaccines for example, they give responses, meaning that tumors regularly shrink when the drug works, while some immunotherapy approaches exert their effect on survival, not tumor size. An advantage over “targeted therapy” is that a single molecular target is not required on cancer cells. Instead, checkpoint inhibitors “release handbrakes” on a body wide level and thus emergence of target-negative clones is less likely resulting in often a longer duration of efficacy. This body-wide effect also explains why these drugs frequently cause auto-immune adverse events. Finally, they are based on hard-core basic research, and the approach is sufficiently new not to seem like something that was already tried and did not work. Because of these reasons, mainstream oncology meetings have started to seem like immunotherapy meetings. Many of the most popular talks are on immunotherapy and checkpoint inhibitors hold the main stage therein.

With all this excitement, it can be forgotten that checkpoint inhibitors currently only work in a subgroup of patients. The frequency of responding patients might be among the highest in melanoma but even after careful patient selection only a third seem to respond to single agent checkpoint inhibitors while about half can respond to combinations of inhibitors, which unfortunately are much more toxic. In most other tumor types the frequency of responding patients appears to be lower than in melanoma and it is not yet known if similar long term survival effects will be seen.

Over the past couple of years it was discovered that checkpoint inhibitors only work in tumors where there is pre-existing antitumor immunity. Specifically, anti-tumor T cells need to be present. A simple T-cell staining might work as a useful biomarker, although more work is needed to understand how important the location and subclasses of T cells are. It probably makes a difference if the cells are intratumorally disseminated, at the invasive margin or just in the tumor periphery. There are many classes of T cells, some of which are suppressive. The difficulty in biomarker development is that representative fresh tissue is difficult to obtain and there might be big differences between different metastases and even within tumor masses.

The presence of anti-tumor T-cells appears to correlate with existence of neoantigens, proteins not encountered in normal cells. It is logical that foreign proteins resulting from de novo mutations would be more easily detected than self-antigens or overexpressed proteins. This may explain why melanoma, lung cancer and urological cancers seem to respond well to checkpoint inhibition. UV light in the former and smoking associated carcinogens in the latter two could explain the high frequency of neoantigens. Since any immune response will result in an immune suppressive counter-response (this is how the body protects itself against autoimmunity and normal tissue damage during immune cytotoxicity), the presence of tumor-reactive T cells and/or neoantigens correlates with mediators of immunosuppression, such as PD-L1. The currently most popular checkpoint inhibitors block the interaction between PD1 and PD-L1.

Unfortunately, when tumors lack neoantigens and the associated tumor infiltrating lymphocytes, checkpoint inhibitors don’t seem to work. In most cancer types the majority of tumors fall into this category. Can this situation be solved ? Certainly. There are powerful ways to induce T cells against the tumor. Some chemotherapeutics may be able to achieve this goal. Radiation can cause DNA damage resulting in neoantigens and subsequent T-cell activation. Some targeted therapies seem to result in T-cell infiltrates. Cancer vaccines may be able to induce anti-tumor T cells. However, possibly the most potent approach in this regard is the use of oncolytic viruses.

There are several reasons why oncolytic viruses are the perfect companion for checkpoint inhibitors. Virus replication lyses tumor cells releasing antigens (with different epitopes that are T-cell targets), whether they are intracellular or membrane bound. Viruses are the arch-enemy of the immune system, and actually one of two main reasons why we have cellular immunity in general (the other reason is bacteria). Nothing seems more dangerous to the immune system than viruses. Therefore, epitope recognition becomes more efficient when there are virus derived “danger signals” in the vicinity. The presence of virus can break tumor associated tolerance counteracting local immunosuppression. Tumors are heterogeneous, meaning that different antigens are present in different areas. The virus does not need to know about this; whichever epitopes are relevant are released as the virus penetrates into different areas of tumors. This happens spontaneously as daughter virions are released from exploding tumor cells. Some viruses including adenovirus are known to be able to travel through blood to metastases or reinfection of the same tumor.

Although viral epitopes are usually stronger than tumor epitopes, in fact they help in recognition of the weaker epitopes in a phenomenon known as epitope spreading. While oncolytic viruses per se are able to provoke anti-tumor immunity, they can be made more potent by arming them with transgenes. This field is still young but already some T-cell stimulating arming devices have been described, including interleukin-2 and tumor necrosis factor alpha.

In summary, while checkpoint inhibitors have provided much-needed excitement in the field of oncology, they only work in tumors with pre-existing T-cell immunity. Oncolytic viruses are the perfect tool for induction of such immunity, expanding the range of responding tumors. Emerging human data indicates that the combination is well tolerated as the virus doesn’t seem to add to the toxicity of checkpoint inhibitors and oncolytic immunotherapy in itself causes few side effects. Early efficacy result look very promising and in a few years we might have a combination approach which cures patients whose tumors are beyond current routine therapies.

7 comments:

  1. I was diagnosed of cancer since 2017 and I was taking my medications, I wasn’t satisfied and cured quick i needed to get the CANCER out of my system, I searched about some possible cure for CANCER i saw a comment about Dr Tokubo how he cured CANCER with his herbal medicine, I contacted him and he guided me. I asked for solutions, he started the remedy for my health, he sent me the medicine through DHL SPEED POST. I took the medicine as prescribed by him and 14 days later i was cured from CANCER, Dr. Tokubo truly you are great, do you need his help also? Why don’t you contact him through: (drtokubotemple@gmail.com) or you can also reach him on WhatsApp/phone: +2349037990322 thank you

    DOCTOR TOKUBO CAN AS WELL CURE THE FOLLOWING DISEASE:-

    HIV/AIDS
    HERPES
    CANCER
    EPILEPSY
    HPV
    AND BRING BACK YOUR LOVE ONCE TO YOU

    ReplyDelete
  2. I had 4th stage Adenocarcinoma Lung Cancer with EGFR mutation, I have
    tried different methods of treatment to get rid of this disease but I could
    not, few months ago a friend told me about Dr. Sani's Herbal Medicine that
    Dr. Sani could cure me totally from pain with his herbal herbs and Cancer
    oil, when I heard about his good works from my friend I requested for the
    contact Information of this man, after some days passed as I was always
    praying to God for mercy, I said to myself that God could use this man to
    heal me totally, after giving myself this thought I Immediately contacted
    Dr. Sani on (perfectherbalcure@gmail.com) and I told him about my condition, he responded to me and told me not to
    worry that he was going to prepare his herbal medicine and send to me that
    all I needed was to provide him my home address where he can send my
    medicine to, after some days of deal with Dr. Sani, I received a package
    from the courier service, while I was with this medicine I told Dr. Sani
    that I have received the medicine he sent to me, he gave me prescription on
    how to take the medicine, Today all I can share with you now Is that I have
    been cured permanently from my Cancer Disease. Is been 4 Months and I have
    not experience the symptoms again, God has used Dr. Sani to do some great
    works in my life, I'm a living testimony of Dr. Sani's Root and Herbs
    Medicine, Please contact him for help on (perfectherbalcure@gmail.com)
    This Man can help you get cured no matter the Sickness you have, why not contact
    him now and start to live a healthy life again.
    Email: perfectherbalcure@gmail.com
    Whats-app: +2348118184266

    ReplyDelete
  3. This comment has been removed by the author.

    ReplyDelete
  4. Immunotherapy, a type of cancer treatment designed to eradicate disseminated cancer by harnessing the potential of the immune system. Immunotherapy agents do not directly attack the tumour but instead mobilize the immune system -this can be achieved through various approaches that utilize adaptive or innate immunity. checkpoint inhibitors

    ReplyDelete
  5. I have been casting spells for many years and I have helped many people, I might be able to help you too. I am honest, and I genuinely care for all the clients who choose me to cast a spell for them.


    If you have any questions about Love, Money, curse, protection, bad luck, divorce, court cases, or about me please call or email me. I really want you to feel comfortable before moving forward with any spells, or other services. I will take the time to explain things to you and provide you with honest advice, to what is best for your situation. I will not pressure you into having a spell cast, I will leave that decision up to you, and when or if you decide to move forward, I might be able to help you.
    I will respect your Privacy. I will not seek to obtain any of your personal information beyond what you might voluntarily offer and all information you might give me including emails, phone numbers and photos will remain private and confidential.
    I perform my Rituals only at night between the hours of 0.00 - 0.59 (South African time) lasting 1 hour but of course, this depends on the nature of the ritual, some rituals might take hours and can also become necessary to be performed at specials places like; flowing streams, cemeteries and other places dictated by the gods.
    I do not want anyone to be under any illusions about my spells and its numerous rituals. Real and effective Voodoo is no child's play, it is expensive because, after the rituals, I will have to destroy all the materials involved by fire and the ashes scattered over a flowing stream or river.
    You will get what you seek.But please understand this might take a lot of time and that individual results may vary. contact +27663492930, greatogudugu@gmail.com

    Herbal cure for Following DISEASES,this is not scam is 100% Real.

    -HPV
    -DIABETES
    -PENIS ENLARGEMENT AND WEAK ERECTION
    -VIRGINA PROBLEM
    -WHOOPING COUGH
    - HEPATITIS B
    -FORDYCE SPOT
    -COLD SORE
    -ALS
    -LOWER RESPIRATORY INFECTION
    -LOW SPERM COUNT
    -MRSA(METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS
    -ZIKA VIRUS
    -HIV
    -STROKE
    -IMPOTENCE
    -PILE
    -HYPERTENSION
    -LOW SPERM COUNT
    -MENOPAUSE DISEASE
    -ASTHMA
    -CANCER
    -BARENESS/INFERTILITY
    -PCOS
    -SHINGLES
    -VIRAL HEPATITIS/HEPATITIS B
    -FIBROID
    -ASTHMA
    -SICKLE CELL
    -TINNITUS
    -BARENESS/INFERTILITY
    -DIARRHEA and so on...

    ReplyDelete
  6. I was diagnosed with stage 3 breast cancer in August of 2010. A precious friend told me about Dr Itua Herbal Center in West Africa,She gave me his contact number and email address,I contacted him quickly so he give me guaranty that his herbal medicine will cure my cancer and i will be heal forever I said Okay.I ask him about the process for the cure,he ask me to pay for the fees which i did and within 7 working days he sent me the herbal medicine then he instructed me on how to drink it for two weeks to cure.I told Gomez my friend about the herbal medicine so he gave me go ahead to drink it.So after drinking it for two weeks i was cured I'm so grateful and i promise i will recommend anyone with cancer to him and that what i'm doing.Dr Itua Herbal Medicine makes me believes there is a hope for people suffering from,Parkinson's disease,Schizophrenia,Cancer,Scoliosis,Bladder Cancer,Colorectal Cancer,Breast Cancer,Kidney Cancer,Leukemia,Lung Cancer,Skin Cancer,Uterine Cancer,Prostate Cancer,Fibromyalgia,a
    Syndrome Fibrodysplasia ,Epilepsy Dupuytren's disease, Diabetes ,Coeliac disease, Angiopathy, Ataxia,Arthritis,Amyotrophic Lateral Sclerosis,Alzheimer's disease,Adrenocortical carcinoma.Asthma,Allergic diseases.Hiv_ Aids,Herpes,Inflammatory bowel disease ,Copd,Diabetes.
    Here Is His Contact Info......[Email...drituaherbalcenter@gmail.com/Whatsapp...+2348149277967]

    ReplyDelete
  7. Hello I'm Donna Mary, I'm giving a testimony about Dr. Anselm Adodo; the great traditional herbal doctor. He has the cure to all manner of diseases, he cured my Cancer Disease.
    Cancer doesn't have to be a death sentence even if you have stage IV cancer. For many people, Cancer feels like a death sentence. Doctors tell us that the only way to treat cancer is by using chemo, radiation, or surgery. They pressure us to take standard treatments. We are to believe that we will die if we don’t use these procedures. Chemo only has an average survival rate of 2% and is often deadlier than cancer itself. The survival rate of stage IV cancer is low when you use standard treatments.
    And then there are natural remedies that seek to treat cancer by fixing the imbalances. This way of treating cancer is frowned upon by doctors and pharmaceutical companies. Many people are afraid of trying natural remedies because there is not much research done.
    Though I went through different website I saw different testimonies about different spell casters and herbalist, I was like: 'Many people have the Cancer cure why are people still suffering from it?'
    I thought of it, then I contact Dr. Anselm Adodo via email, I didn't believe him at first, I just wanted to give him a try, He replied my mail and Needed some Information about me, then I sent them to him, he prepared it (CURE) and sent it to Airfreight Online Courier Service for delivery, he gave my details to the Courier Office, they told me that 3-5 days I will receive the package and I took the medicine as prescribed by him and I went for check-up 2 weeks after finishing the medicine, I was healed of Cancer, If you are a CANCER Patient, I would like you to contact him; and I will try my possible best to make sure that everyone infected with any diseases are cured. When you contact him, make sure you tell him that I referenced you...
    Contact Via: dranselmadodo@gmail.com
    Whatsapp: +2348112872363
    Contact me on donnamary121@gmail.com

    ReplyDelete