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Homepage – Forum Forums Research, Clinical Trials, and New Treatments Natural Killer (NK) cells enhancement for BCG Unresponsive

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  • #43040
    Joe
    Participant

    On January 8, 2020, the FDA approved pembrolizumab (Keytruda; Merck) for the treatment of patients with Bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non–muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.    Pembrolizumab is one of several FDA approved immunotherapies in recent years.  Most FDA approved immunotherapies are for advanced bladder cancers.     Pembrolizumab is the first approved immunotherapy for non-muscle invasive bladder cancer.  Cancer is the result of accumulation of key gene mutations.  Bladder cancer is known to have many key gene mutations.  In a sense, bladder cancer cells are injured cells and often send signals for the help.   Our innate immune cells, which either reside near the cancer cells or circulating blood detect the cancer (injured) cells and try to kill the cancer cells.  Also, those innate immune cells pick up pieces of the cancer cells and deliver it to lymphatic system, such as lymph nodes, the thymus and the spleen for help.  Upon receiving the pieces of the cancer cells (antigen),  B-cells and T-cells are activated specific for the antigen.   T-cells are cell mediated immune cells and kill the cells which present the specific antigen, in this case cancer cells.   The problem is that one of hall marks of cancer is that they have evolved to be able to hide and evade the attack from our immune system.  One way is for cancer cells and surrounding microenvironment to send signals to T-cells not to attack them.  When the signal receiver of T-cells receive the signal from cancer cells,  T-cells do not attack the cancer cells.     Immunotherapy drug either enable T-cells to attack the cancer cells by either  inhibiting the signal from the cancer cells or inhibiting signal receiver of T-cells.    Immunotherapy drugs which inhibit the signal from the cancer cells are called PD-L1 immune check point inhibitor, and the drug which inhibit the signal receiver of T-cells are called PD-1 immune check point inhibitor.   PD-1  immune check point inhibitors are for example Pembrolizumab (Keytruda; Merck), Nivolumab (Opdiovo;Bristol Myers Squibb), and PD-L1 immune check point inhibitors are for example, Atezolizumab(Tecentriq;Roche) and Avelumab (Bavencio; Pfizer).

    They have found that one of reasons why BCG does not work for some patients is because bladder cancer cells and surrounding micro environment of those patients had high expression of PD-L1 immune check point inhibitors even though BCG treatment activated T-cells and came near the cancer cells.     So two clinical trials for BCG unresponsive started.  One trial used Pembrolizumab  PD-1 immune check point inhibitor and the other used Atezolizumab PD-L1 immune check point inhibitor.  The efficacy for two different immune checkpoint inhibitors were similar, but because of the design of the clinical trials, Pembrolizumab  PD-1 immune check point inhibitor was approved but the clinical trial for Atezolizumab PD-L1 immune check point inhibitor was stopped.

    The efficacy of Pembrolizumab  PD-1 immune check point inhibitor for BCG unresponsive was 38.8% at 3 month and 27% at 14 months.    It was approved by 9 to 4.

    Since then, MERCK started another Phase 2 clinical trial (KEYNOTE-057 ) for Pembrolizumab +BCG for BCG unresponsive, with the result is pending.

    Meanwhile,  In January, MERCK announced the discontinuation of the business of manufacturing Intron A (TM) – Interferon Alpha-2b.  MERCK was the sole supplier of Interferon Apha-2b.    Interferon alpha-2b has been used by combining with BCG to treat BCG Unresponsive NMIBC.      Interferon alpha-2b was relatively inexpensive at $1,000.00 where Pembrolizumab (Keytruda) costs about $10,000 per dose.  Also, Interferon alpha-2b was given intravesical where Pembrolizumab was administered intravenously.     Anyway, as MERCK had dropped Interferon alpha02b business, we have lost a treatment for BCG unresponsive NMIBC.

    Luckily,  there is a new kid on the block to treat BCG Unresponsive.  The treatment is BCG + proprietary Il-15 based Natural Killer cells primer.

    If you recall the BCC webinar by Dr. Madhuri Koti back in Marck 2022, she showed mechanism of actions of how BCG invokes our immune system and our immune cells kill BCG infected cancer cells.  One of  immune cells  which kill cancer cells were T cells.   As explained first,  our cancers have evolved to evade the attack from T-cells, and immune check point inhibitor immunotherapy had shown to its efficacy to enable T-cells to attack those cancer cells.   Dr. Koti also explained  that Natural Killer(NK) cells also kill  BCG infected cancer cells.   NK cells are innate immune cells.  Unlike T-cells which are adopted immune cells which attack only cells with specific antigen,  NK cells does attack any pathogens including BCG infected cancer cells.   However, cancers have evolved not to be attacked by NK cells also.    A pharmaceutical company Immune-Bio specialized in innate immune system and the company developed the drug to stimulate inactive NK cells, kills bladder cancer cells.   The drug is based upon Interleukin-15  (IL-15) as an activator of NK cells which are inactive near cancer cells.

    The result of Phase 2/3 clinical trial of BCG +  Anktiva  showed a complete response rate 72% at any time (3 3 or 6 months), which compares favorably to 41% of FDA approved pembrolizumab.

    I am sure the price will be much more expensive than Interferon alpha-2b, but the administration of the new drug Anktiva +BCG is down intravesical, which is similar to how BCG+Interferon alpha 2b is administered.

    In December 2019, the FDA granted ImmunityBio Breakthrough Therapy Designation based upon interim Phase 2 data indicating the primary endpoint of the trial was already met, so we hope to see IL-15 based NK cell activator Anktiva to be approved soon as replacement for BCG+Interferon alpha-2b.

    I will try to post next with the links to the references.

    best

     

     

     

     

     

     

    #43042
    Joe
    Participant

    BCG Mechanism of Actions.  It lists immune mediated cytotoxicity which kill cells which internalized BCG bacteria as follows

    NK cells (Natural Killer cells) – Innate immune cells

    CD8+ Lymphocytes (Killer T-cells) – Adopted immune cells

    Macrophages – Innate immune cells

    TRAIL (granulocyte) – TNF (Tumor Necrosis Factor)  related apoptosis-inducing ligand

     

    BCG Mechanism of Actions

    #43045
    Joe
    Participant

    Links related to this subject

    Natural Killer cells immunotherapy for BCG unresponsive  by ImmunityBio 

    ir.immunitybio.com/news-releases/news-release-details/immunitybio-submits-biologics-license-application-n-803-plus-bcg?field_nir_news_date_value[min]=

     

    Videosof how Killer T-cells (CD8+) kill cancer cells

    http://www.youtube.com/watch?v=ntk8XsxVDi0

    Videos of how inactive NK cells kill ovarian cancer cells when inactivated NK cells are activated by INKmune which primes NK cells with IL-15.

    http://www.youtube.com/watch?v=CKhsHaKDFo4

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    #43047
    Joe
    Participant

    Sorry, there are several errors in my postings.

    There are two different companies with similar name and I got confused.   One company is ImmunityBio and the other company is INmune  bio.

    ImmunityBio of which the head office is located in Culver City, California was founded in 2014 to create innovative immunotherapies.  Their immunotherapy is based upon Natural Killer (NK) cells.    ImmunityBio is the company who developed IL-15 based drug Ankitiva which with the combination with BCG has shown higher efficacy than Pembrolizuymab (keytruda) alone in treating BCG Unresponsive high risk non muscle invasive bladder cancer.

    INmune Bio was was established in 2015. The company is located in Florida.  The company focused on modulating components of the innate immune system to activate a response against cancer and Alzheimers.   INmune Bio’s cancer drug also utilizes Natural Killer (NK) cells.   The company explains how INKmune works as blow.     INKmune is on Phase 1 clinical trial to treat ovarian cancers.   No drugs for bladder cancers have been developed.

    – Cancer patients have lots of NK cells … but they ignore the cancer

    – INKmune converts patient’s resting NK cells into cancer killing memory like NK cells

    – Effects of a single course of therapy last for at least 4 months

    Note that Ankitiva of ImmunityBio to treat bladder cancer and INKmune of Immune Bio to treat ovarian cancer both utilize IL-15 to activate inactive NK cells to kill cancer cells.

    See how INKmune activates  NK cells  to kill ovarian cancers    http://www.youtube.com/watch?v=H3joxXidb3M

    best

    #43239
    Joe
    Participant

    ASCO – American Society of Clinical Oncology annual meeting is being held (June 3- June 7) in Chicago.  30,000 attended.
    The preliminary result of the clinical trial “QUILT 3032” NK cell immunotherapy by  Immunity Bio was presented by Dr. Karim Chamie. the director of Institute of Urologic Oncology at UCLA. I believe Dr. Chamie is an investigator for the clinical trial QUILT for  NK cell immunotherapy by  Immunity Bio.

    The study compared the efficacy at Phase 2 between QUILT 3032  and  KEYNOTE-057 Immune check point inhibitor – Pembrolizumab (KEYTRUDA(TM)) by MERK for BCG unresponsive.

    High lights in the presentation were the percentage of patients who had cystectomy during the clinical trials were 16% of the patients in QUILT 3032 ended up having cystectomy and 42% of the patients in KEYNOTE–057 ended up having cystectomy.

    It is noted that the QUILT TRIAL was BCG + NK cells immunotherapy.  KEYNOTE-057 was Pembrolizumab only.
    clinicaltrials.gov/ct2/show/NCT03022825

    MERCK is now conducting another clinical trial KEYNOTE-676 which is to test efficacy of BCG + Pemrolizumab (Keytruda) for BCG Unresponsive.

    clinicaltrials.gov/ct2/show/NCT03711032

    It is also noted that though QUILT 3032 clinical trial test sites are all in the US,  KEYNOTE-676 clinical trials have several test sites in Canada.

    anada, British Columbia
    Exdeo Clinical Research Inc. ( Site 0165)
    Recruiting
    Abbotsford, British Columbia, Canada, V2T 1X8
    Contact: Study Coordinator    6048515667
    Silverado Resarch Inc. ( Site 0155)
    Recruiting
    Victoria, British Columbia, Canada, V8T 2C1
    Contact: Study Coordinator    2505929988
    Canada, New Brunswick
    Horizon Health Network ( Site 0160)
    Recruiting
    Moncton, New Brunswick, Canada, E1C 6Z8
    Contact: Study Coordinator    5068574780
    Canada, Ontario
    Princess Margaret Cancer Centre ( Site 0153)
    Recruiting
    Toronto, Ontario, Canada, M5G 2M9
    Contact: Study Coordinator    4169462246
    Canada, Quebec
    CIUSSS du Saguenay-Lac-St-Jean ( Site 0164)
    Recruiting
    Chicoutimi, Quebec, Canada, G7H 5H6
    Contact: Study Coordinator    4185411000
    CIUSSS de l Est de L Ile de Montreal – Hopital Maisonneuve-Rosemont ( Site 0157)
    Recruiting
    Montreal, Quebec, Canada, H1T 2M4
    Contact: Study Coordinator    5142523400×5766
    Centre intégré de cancérologie du CHU de Québec Université Laval, Hôpital de l’Enfant-Jésus ( Site 0
    Recruiting
    Quebec City, Quebec, Canada, G1J 1Z4
    Contact: Study Coordinator    418525444420414
    CHUS – Hopital Fleurimont ( Site 0152)
    Recruiting
    Sherbrooke, Quebec, Canada, J1H 5N4
    Contact: Study Coordinator    8193461110×12827

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    #43243
    Joe
    Participant

    #43244
    Joe
    Participant

    #43245
    Joe
    Participant

    Sorry, the forum software did not have 3 images in the same posting, so I had to post one image at a time.

     

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