Immunotherapy on Cancers

choi

(1) On Aug 5, 2021 the SundayStyes section of New York Times had a lookback on four past writers of its Modern Love column, wose introduction stated in part: "And what happened to Mary Elizabeth Williams, who, after reuniting with her husband, learned she might have only months to live?  (Well, she still lives.) Another of the four was:

Stepping Forward into Marriage, Round 2; 'The mortality for being a human being is 100 percent.'
https://www.nytimes.com/2021/08/ ... abeth-williams.html

Note:
(a) Mary Elizabeth Williams, About. undated.
https://www.maryelizabethwilliams.net/about

the first four paragraphs:

"On August 10, 2010, my Facebook status update was 'Best summer ever.' On August 11, I learned I had malignant melanoma.

"A few days later,I underwent surgery that removed a 5 cm circle from the top of my head. I now rock a great combover, but my tonsure is even fiercer.

"A year after my surgery, I was diagnosed with melanoma again [ie, had a recurrence]. The cancer had broken off and spread to my lung, and I had a subcutaneous tumor on my back, which meant that it was getting very bad quickly. My oncologist helpfully informed that 'Stage 4 isn't what it used to be,' which is good, because metastatic melanoma traditionally means you're going to be dead pretty soon.

"I was lucky enough to enter a Phase 1 immunotherapy trial at Memorial Sloan Kettering, becoming one of the first human subjects in the world to try out the treatment now known as Opdivo. Three months later, I had no evidence of disease. (* * *

(b) Mary Elizabeth Williams; Melanoma |  Diagnosed 2010. 'There's no question in my mind that immunotherapy saved my life.'
Cancer Research Institute, undated
https://www.cancerresearch.org/p ... es/mary-elizabeth-w
("In late 2011, that thought loomed in Mary Elizabeth's mind as she prepared to begin conventional treatment for what all medical sources told her was a terminal illness. Then, at the last minute, she learned she was eligible for clinical trial of a promising new immunotherapy being conducted by Jedd Wolchok, MD, PhD, at Memorial Sloan Kettering Cancer Center in New York City. The trial was a study of two checkpoint inhibitor drugs, ipilimumab and nivolumab (made by Bristol Myers-Squibb), for patients with metastatic melanoma. Both drugs are [monoclonal] antibodies directed at specific “braking” molecules, called checkpoints, on immune cells. By 'taking the brakes off' the immune response, the drugs enable a more powerful anti-cancer response.  Mary Elizabeth began treatment with the two immunotherapy drugs in November 2011. By January 2012, she knew the treatment was working")
(i) Tasuku HONJO 本庶 佑 (1942- ; MD in 1966 and PhD in 1975, both from Kyoto Univ)
(ii) Cancer Research Institute
https://en.wikipedia.org/wiki/Cancer_Research_Institute  
(a non-profit organization)
is different from National Cancer Institute, a constituent institute of National Institute of Health (NIH).
(iii)
(A) ipilimumab (Bristol-Myers Squibb trademark: Yervoy; binding CTLA-4) was developed by James P Allison of University of California, Berkeley. It went through clinical trial at Princeton, New Jersey-based Medarex, Inc.
(ii) nivolumab (Bristol-Myers Squibb trademark: Opdivo; binding PD-1) was developed by Changyu Wang (does not use Chinese name, even in China's media; PhD Univ of Colorado, BS Wuhan Univ), a scientist (2001-2009) working under another Alan J Korman at Medarex, which was acquired by Bristol in 2009). The en.wikipedia.org for nivolumab attributes the invention of nivolumab to Dr Wang alone, but mostly accolades are to Korman.

Merck's Keytruda, which is seen on television commercials a lot, is another monoclonal antibody that binds PD-1 also.  

choi

(2) Discovery of Cancer Therapy by Inhibition of Negative Immune Regulation. Nobel Prize in Physiology or Medicine, 2018
https://www.nobelprize.org/prize ... vanced-information/
("is awarded to James P Allison and Tasuku Honjo")

Quote:

"In 1987, incidentally the same year as the CD28 [CD stands for 'Cluster of differentiation' -- a cell surface marker] gene was isolated, the cDNA for a T cell-­expressed, CD28-­related molecule, CTLA-­4 (cytotoxic T lymphocyte antigen 4), also named CD152, was cloned in the laboratory of Pierre Golstein [of France] (Brunet et al., 1987). The function of CTLA-­4 was unknown, but structurally both CD28 and CTLA-­4 belong to the immunoglobulin superfamily. * * * CTLA-­4, similar to CD28 [both CTLA-4 and CD28 are on the surface of T cell; CD28 + B7 stimulate T cell but CTLA-4 + B7 inhibit T cell], binds to B7 [on the surface of antigen-presenting cell (APC), a fancy name for macrophage], but with higher affinity.

"While some investigators used this new knowledge [about CTLA-4's serving as a brake on T cells; by somehow enhancing CTLA-4] to develop treatments for autoimmunity (Lenschow et al., 1992), Allison followed another path [blocking CTLA-4's binding B7, which conceptually would be easier than enhancing CTLA-4]. * * * he intended to find a cure for cancer. He attempted to block the negative effects that CTLA-­4 induced, thereby unleashing an immune response. * * * the strategy was not selective for a particular type of tumor, but was in essence universal [theoretically against all types of cancers; it worked in mice in 1994]. * * * [Allison's experiments on mice showed] rejection was followed by durable tumor immunity

"Allison eventually managed to establish collaboration with Alan Korman from the small biotech company, Medarex[, Inc (based in Princeton, New Jersey)] * * * [to produce, in mice, HUMAN (so as not to be rejected by human patients)] anti-­CTLA-­4 IgG1 monoclonal antibody named MDX-­010 was developed in 1999, later named ipilimumab (Wolchok et al., 2013). The company Bristol-­Myers Squibb subsequently acquired Medarex * * * In the first-­in-­man study MDX-­010 was given to 9 patients [with melanoma] * * * A special feature was the observation that treatment initially could even increase the tumor volume * * * owing to the infiltration of immune cells, rather than reducing it immediately, as [reduction in tumor volume is] usually seen with chemo-­ or radiotherapy.

"The second discovery awarded by this year's Nobel Prize also originated in basic, curiosity- driven research, not primarily oriented towards cancer. PD-­1 (CD279) was identified and cloned by Tasuku Honjo's group at Kyoto University in Japan already in the early 1990s (Ishida et al., 1992) * * * before Allison's discovery of CTLA-­4 inhibition to treat cancer. At the time, Honjo and colleagues assumed that PD-­1, identified by subtractive hybridization [eg, by creating cDNA library from dying cells and another cDNA library from normal cells, and conceptually hand picking those cDNAs that were more abundant in dying cells; this strategy does not always work and did not work here, as PD-1 was not related to dying cells, which were targets of T cells] to isolate mRNAs overexpressed in dying mouse cells, would be involved in pathways regulating apoptosis. Hence, they used the acronym PD (for Programmed Cell Death). The open reading frame predicted a protein with a transmembrane region, distantly related to the immunoglobulin gene superfamily. * * * The function of PD-­1 remained elusive for many years. Honjo [ten years later figured out that PD-1 on T cells] * * * Honjo concluded that PD-­1, similar to CTLA-­4, acts by negatively controlling immune responses. * * * In parallel, Honjo and colleagues had engaged in a hunt for the ligand of PD-­1. They identified it together with the groups of Gordon [J] Freeman [of Dana Farber Cancer Institute in Boston] and Clive Wood (Freeman et al, 2000) and it was named PD-­1 ligand (PD-­L1). A human equivalent of the molecule had been described already the year before in the laboratory of Lieping Chen [陈列平; MD (from 福建医科大学), PhD (from private Drexel University in Philadelphia), is at Yale] (Dong et al., 1999) * * * The Freeman et al report (2000) was also the first to discuss the possibility that some tumors may use PD-­L1 to inhibit an antitumor immune response, based on the observation that the molecule was expressed, not only by macrophages * * * but also by certain cancer cells. * * * [sectional heading:] PD-­1 blockade [with monoclonal antibody, to prevent to from binding PD-1L on surface of cancer cells] as a treatment of cancer

"While the outcome of multiple studies suggest that ICIs [ICI stands for immune checkpoint inhibitor] against PD-­1 or its ligand, PD-­L1, yield better treatment effects as compared to anti-­CTLA-­4, combined therapy with blockade of both CTLA-­4 and PD-­1 seems to induce an even stronger anti-­tumor effect in both melanoma (Wolchock et al., 2013; Wolchock et al., 2017), depicted in Fig. 5, and in renal cell carcinoma (Motzer et al., 2018), possibly because of different mechanisms of action. As expected, there are severe [heed this word 'severe'] side effects in the form of autoimmunity [side effects listed] * * * As with many cancer treatment modalities, the adverse reactions associated with immune checkpoint therapy can in some instances be fatal.


(3) Both ipilimumab and nivolumab had their initial clinical trials on (human stage-IV) melanoma. This is because human melanoma is quite unusual among cancers.
(a) Former President Jimmy Carter (at the time 91 years old) was diagnosed in August 2015 with stage IV melanoma (metastasis to liver and brain). He received radiation first and then pembrolizumab (Keytruda). By December, that year the cancer was gone, which has not relapsed.
(b) Melanoma in humans and mice is especially susceptible to various immunotherapies, for reasons we still do not know why.

My comment: This is an important topic, so I have spent a week on this. Being an immunologist myself, I wish to point out that we do not know what human immune system sees in a cancer that makes the immune system attack the cancers. That is, what surface molecules that distinguish themselves from those of normal cells that enable the human immune system to attack cancer cells but not normal cells. In theory, surface molecules on cancer cells are no different from those on normal cells.