Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies.

More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival.

Exploiting autoimmunity unleashed by low-dose immune checkpoint blockade to treat advanced cancer.

As a result of the cancer immunotherapy revolution, more than 2000 immuno-oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co-inhibitory signals. Unfortunately, manipulation of the co-inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune-related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA-4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self-tissues. The irAEs are very similar to that of a chronic graft-versus-host-disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft-versus-malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto-GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune-suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof-of-principle of a low-dose-combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.

Control of minimal residual cancer by low dose ipilimumab activating autologous anti-tumor immunity.

In this perspective article, we address the controversy regarding the safety-efficacy issue in ipilimumab trials. While the CTLA-4 blockade interrupted T-cell pathways responsible for immune down-regulation and mediated regression of established malignant tumors in a minority of patients, this has to be weighed against the immune related adverse events (irAEs) suffered by the majority. Based on two groundbreaking but neglected proof-of-principle papers that demonstrated augmented graft-vs.-malignancy (GVM) effect that reversed the relapse of malignancy without worsening the graft-vs.-host disease (GVHD) by a CTLA-4 blockade, here we suggest a therapeutic paradigm shift, which may help break the impasse and resolve this timely issue in oncology.

Interesting possibilities to improve the safety and efficacy of ipilimumab (Yervoy).

As predicted, an anti-CTLA-4 mAb (ipilimumab) on binding to T lymphocytes breaks down immune-tolerance. Thereby, it was hoped, tumor-specific-T cells would be freed for a sustained attack on cancer cells. Data on ipilimumab treatment in 1498 patients with advanced melanoma (in 14 phase I-III trials) has shown immune-related adverse events (irAEs) in 64.2% of the patients consistent with tolerance breakdown. However, there is no evidence that the antitumor effects via a CTLA-4 blockade are attributable to T cells specifically targeting tumor cells. In fact, several trials indicate a possible correlation between grade 3 and 4 irAEs with clinical efficacy of ipilimumab; tumor regression may be associated with autoimmunity development. Therefore, we suggest a new treatment paradigm. The non-tumor specific pan-lymphocytic activation should be exploited by a 'pretargeting' approach proven successful in radioimmunodetection and radioimmunotherapy. First, an anti-tumor mAb conjugated with streptavidin (StAv) should be administered to be followed by the delivery of biotin-labeled anti-CTLA-4 mAb. This schedule has the virtue of endowing T cells with the ability to travel to tumor sites without prematurely succumbing to apoptosis, while streptavidin's ultra-high affinity for biotin (K(D), 10⁻¹5 M) ensures capturing all T cells binding biotin labeled anti-CTLA-4. Using the law of mass action, we calculated that following administration of ipilimumab at >1 mg/L concentration (∼5 mg per patient ∼70 kgbw), the immense forces of the immune system liberated by the anti-CTLA-4 antibody blockade would then be focused with laser sharp accuracy on tumor cells without collateral damage to normal host cells.

Ipilimumab (Yervoy) and the TGN1412 catastrophe.

The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy) immune regulatory therapy was based on the premise that "Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication…" (Weber, 2009). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer. T cells lost their ability to discriminate between self and non-self. Thus, tolerance to self tissues was broken in ∼70% of the patients. In the recent industry-sponsored phase III clinical trial of ipilimumab, 147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine. Promoters of ipilimumab appear to be unmindful of the clinical trial catastrophe in London. Then, a humanized "superagonist" anti-CD28 monoclonal antibody, TGN1412, which "preferentially" activated regulatory T cells, at a higher dose, also activated all CD28 positive T cells. This precipitated a "cytokine storm" leading to life-threatening multiple organ failure in the six healthy human volunteers. Neither anti-CD28 nor anti-CTLA-4 therapies rely on antigen-specificity. Both release free antibody into the body against common molecular targets that are expressed on the targeted as well as on the non-targeted T cells. At lower antibody doses specific T cells are preferentially activated. With increasing antibody dose, however, the kinetics of the interaction is pushed in favor of widespread non-specific T cell expansion. Using the law of mass action we calculated that the vast majority of the CTLA-4 receptors on all activated T cells (including melanoma specific T cells) in the phase III clinical trial of ipilimumab will have been saturated. This would explain the runaway immune response observed. The conclusions drawn by the authors of the ipilimumab trial paper could bear an independent inspection and reassessment concerning the validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer.

Sonodynamic and photodynamic therapy in advanced breast carcinoma: a report of 3 cases.

Photodynamic therapy (PDT) is an established therapeutic method, first approved by the FDA for certain kinds of cancer in 1998. There are also increasing data to show that a related procedure, sonodynamic therapy (SDT), is a promising new modality for cancer treatment. Here, the authors report clinical results in 3 advanced refractory breast cancer patients who were treated using a combination of sonodynamic and photodynamic therapy (SPDT), along with conventional therapies. All 3 patients had pathologically proven metastatic breast carcinoma. These widely disseminated carcinomas had ultimately failed to respond to conventional therapy. A new sensitizing agent, Sonoflora 1 (SF1) was administered sublingually; then, after a 24-hour delay, patients were treated with a combination of light and ultrasound. All patients had significant partial or complete responses. SPDT is a promising new therapeutic combination for the treatment of breast cancer.

The life and times of John Beard, DSc (1858-1924).

The British developmental biologist John Beard, DSc (1858-1924) is little remembered today. Yet, he made outstanding contributions to the life sciences. Beard deserves to be included among the leading biologists of the late 19th and early 20th century. He has been hailed as a forerunner of the present-day theory of the cancer stem cell (CSC). He was the first to point to the parallels between cancer and the trophoblastic cells that envelop and nourish the embryo, characterizing cancer as "irresponsible trophoblast." He pointed out that the initiation of fetal pancreatic function coincided with a reduction in the invasiveness of trophoblast, which otherwise might progress to clinical cancer (ie, choriocarcinoma). Based on the above propositions, he recommended the therapeutic use of pancreatic enzymes in treating cancer and other diseases. This therapy created a worldwide controversy, and although rejected in his day, persists in the world of complementary and alternative medicine (CAM) today.

Enzymes, trophoblasts, and cancer: the afterlife of an idea (1924-2008).

In the early 20th century, advocacy of the enzyme therapy of cancer was primarily the work of one man, John Beard, DSc (1858-1924). He and his collaborators made a determined effort to establish this mode of therapy, especially in the years 1905 to 1911. Despite a brief flowering of international interest, Beard's efforts came to naught. During the 20th century, there was a succession of American researchers who continued to investigate this topic. This included Marshall William McDuffie, MD (1882-1945), Frank LeForest Morse, MD (1876-1953), Franklin Lloyd Shively, MD (1887-1971), and William Donald Kelley (1926-2005). In central Europe, India, and other parts of the globe, the use of pancreatic enzymes as an adjuvant treatment for cancer has become a fairly routine practice, at least among those doctors who utilize complementary and alternative medicine (CAM). It is also a well-established method for reducing inflammation and mitigating the adverse effects of cytotoxic treatment.

An annotated bibliography of works by John Beard.

This article provides a bibliography of the scientific publications of John Beard, DSc (1858-1924). Beard was an English embryologist and cancer researcher of the late 19th and early 20th century, who devised the trophoblastic theory of cancer, a forerunner of today's theory of cancer stem cells. Beard was the author of more than 100 scientific articles and monographs, as well as the book The Enzyme Treatment of Cancer (1911). This is the first bibliography ever compiled of his scientific publications.

Do antioxidants interfere with radiation therapy for cancer?

Despite recent comprehensive review articles concluding that supplemental antioxidants do not undermine the effectiveness of cytotoxic therapies, the use of antioxidants during cancer treatment remains controversial. Many oncologists take the position that antioxidants by their nature undermine the free radical mechanism of chemotherapy and radiotherapy and should therefore generally be avoided during treatment. For their part, many integrative practitioners believe that antioxidants taken during cancer treatment not only alleviate some of the adverse effects of that treatment but also enhance the efficacy of cancer therapy. Until recently, research attention has focused primarily on the interaction of antioxidants with chemotherapy; relatively little attention has been paid to the interaction of antioxidants with radiotherapy. This article reviews the clinical literature that has addressed whether antioxidants do in fact interfere with radiation therapy. Studies have variously investigated the use of alpha-tocopherol for the amelioration of radiation-induced mucositis; pentoxifylline and vitamin E to correct the adverse effects of radiotherapy; melatonin alongside radiotherapy in the treatment of brain cancer; retinol palmitate as a treatment for radiation-induced proctopathy; a combination of antioxidants (and other naturopathic treatments) and external beam radiation therapy as definitive treatment for prostate cancer; and the use of synthetic antioxidants, amifostine, dexrazoxane, and mesna as radioprotectants. With few exceptions, most of the studies draw positive conclusions about the interaction of antioxidants and radiotherapy. Although further studies are needed, the preponderance of evidence supports a provisional conclusion that dietary antioxidants do not conflict with the use of radiotherapy in the treatment of a wide variety of cancers and may significantly mitigate the adverse effects of that treatment.

Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants?

In September 2005, CA: A Cancer Journal for Clinicians published a warning by Gabriella D'Andrea, MD, against the concurrent use of antioxidants with radiotherapy and chemotherapy. However, several deficiencies of the CA article soon became apparent, not least the selective omission of prominent studies that contradicted the author's conclusions. While acknowledging that only large-scale, randomized trials could provide a valid basis for therapeutic recommendations, the author sometimes relied on laboratory rather than clinical data to support her claim that harm resulted from the concurrent use of antioxidants and chemotherapy. She also sometimes extrapolated from chemoprevention studies rather than those on the concurrent use of antioxidants per se. The article overstated the degree to which the laboratory data diverged in regard to the safety and efficacy of antioxidant therapy: in fact, the preponderance of data suggests a synergistic or at least harmless effect with most high-dose dietary antioxidants and chemotherapy. The practical recommendations made in the article to avoid the general class of antioxidants during chemotherapy are inconsistent, in that if antioxidants were truly a threat to the efficacy of standard therapy, antioxidant-rich foods, especially fruits and vegetables, ought also be proscribed during treatment. Yet no such recommendation is made. Furthermore, the wide-scale use by both medical and radiation oncologists of synthetic antioxidants (eg, amifostine) to control the adverse effects of cytotoxic treatments is similarly overlooked. In sum, this CA article is incomplete: there is far more information available regarding antioxidant supplements as an appropriate adjunctive cancer therapy than is acknowledged. Patients would be well advised to seek the opinion of physicians who are adequately trained and experienced in the intersection of 2 complex fields, that is, chemotherapeutics and nutritional oncology. Physicians whose goal is comprehensive cancer therapy should refer their patients to qualified integrative practitioners who have such training and expertise to guide patients. A blanket rejection of the concurrent use of antioxidants with chemotherapy is not justified by the preponderance of evidence at this time and serves neither the scientific community nor cancer patients.

Patient perspectives: Tijuana cancer clinics in the post-NAFTA era.

This article contains observations and historical considerations on cancer and complementary and alternative medicine (CAM) in the Tijuana, Mexico, area. There are approximately 2 dozen such clinics in Tijuana, some of which have been treating international cancer patients since 1963. Among the first clinics to be established were the Bio-Medical Center (Hoxsey therapy), Oasis of Hope (a Laetrile-oriented clinic), and a series of clinics affiliated with the Gerson diet therapy. These original clinics were established mainly by American citizens in response to increased regulation of nonstandard therapies in the United States, particularly after passage of the Kefauver-Harris Amendments to the Food, Drug and Cosmetics Act in 1962. In the 1970s, the Tijuana clinics proliferated with the upsurge of interest in Laetrile (amygdalin). By 1978, 70,000 US cancer patients had taken Laetrile for cancer treatment, and many of those had gone to Tijuana to receive it. The popularity of the Tijuana clinics peaked in the mid-1980s. Although many new clinics opened after then, a dozen have folded in the past 10 years alone. The turning point for the clinics came with passage of the North American Free Trade Agreement (NAFTA), which facilitated greater cooperation among the antifraud authorities of Canada, the United States, and Mexico. In 1994, the tripartite members of NAFTA formed the Mexico-United States-Canada Health Fraud Work Group, or MUCH, whose brief is to strengthen the 3 countries' ability to prevent cross-border health fraud. Under the auspices of MUCH and its members, regulatory crackdowns began in earnest early in 2001. The clinics were also badly affected by the general downturn in travel after 9/11. If these trends continue, many Tijuana clinics are unlikely to survive. Some suggestions are made for how the Tijuana clinics could be reorganized and reformed to minimize the likelihood of governmental actions and to maximize public support. Such reforms center on 5 main areas: (1) research, (2) physical plant, (3) finances, (4) ethics, and (5) education.

Cancer and complementary and alternative medicine in Italy: personal observations and historical considerations.

This article contains observations and historical considerations on cancer and complementary and alternative medicine (CAM) in Italy, a country that has a great tradition in medical research, going back to the Renaissance. However, Italy does not have a strong tradition of using CAM approaches in the treatment of cancer. While surveys show that the Italian population is eager to learn more about CAM, the medical profession there is largely dismissive of these methods. In 1997-1998, the notorious Luigi Di Bella affair occurred in Italy, when a professor of physiology at Modena proposed a nonconventional approach to cancer treatment, based on the off-label use of somatostatin. This treatment found champions in the media and general public but was opposed by most of the medical profession. Although clinical trials later demonstrated that it had no efficacy, the affair divided Italian public opinion and nearly brought down the national government. Italy no longer has prominent proponents of nonconventional treatments in cancer. However, it continues to have innovative scientists who do important work that is consonant with a CAM approach. This article considers the work of 3 such scientists: Paolo Lissoni, MD, of Monza (Milan), who has carried out numerous clinical trials with the pineal hormone melatonin; Giancarlo Pizza, MD, of Bologna, who has done extensive work on the use of transfer factor and other immunomodulators in the treatment of renal cell and other kinds of cancer; and Aldo Mancini, MD, of Naples, who has isolated a mutated form of Mn-SOD-2 from the growth medium of a unique liposarcoma cell line. These scientists have introduced some flexibility into a rigid state-run hospital system by offering patients innovative treatment options in the context of approved clinical trials.

Patient responses to Cytoluminescent Therapy for cancer: an investigative report of early experiences and adverse effects of an unconventional form of photodynamic therapy.

Cytoluminescent Therapy (CLT) is an unconventional form of photodynamic therapy (PDT), utilizing a second-generation chlorophyll-derived photosensitizing agent and whole-body illumination. Starting in late 2002, CLT was administered in Ireland to 48 patients. Illumination with lasers and light-emitting diodes followed the administration of an initial bolus i.v. After returning home, patients continued self-administered treatment using oral agent activated by infrared lamps. CLT proponents claimed that these procedures were beneficial to patients with advanced cancer. An organization devoted to making information on alternative therapies available to the public was engaged to contact these CLT patients and assess the outcome. In informal contacts, patients reported that initial side effects were generally mild and transient. However, especially after commencing self-treatment, many reported unanticipated effects, including fatigue and general weakness, increased pain, cough, dyspnea, diminished appetite and weight loss, tissue necrosis, and other major symptoms. At a minimum of 6 months after initial CLT, no patient has reported an objective response, and some have complained of deterioration on the home treatment. There have been 17 deaths among the 48, with a mean survival after initial treatment among decedents of 4.2 months. CLT, in this group, was a qualified failure, with a high incidence of aftereffects. The mode of action of these aftereffects has yet to be explored. In the future, CLT should be administered to patients only in carefully managed medical facilities, by fully trained and licensed professionals, under the supervision of relevant regulatory agencies, and with meticulous follow-up care.