1 00:00:01,340 --> 00:00:04,320 Speaker 1: Welcome to Stuff You Missed in History Class, a production 2 00:00:04,400 --> 00:00:14,940 Speaker 1: of iHeartRadio. Hello and welcome to the podcast. I'm Tracy V. Wilson. 3 00:00:15,180 --> 00:00:18,459 Speaker 1: And I'm Holly Frey. I don't usually watch the news 4 00:00:18,560 --> 00:00:21,660 Speaker 1: on television, but I do at my parents' house because 5 00:00:21,700 --> 00:00:25,110 Speaker 1: my parents watch it. Oh. And I was visiting them 6 00:00:25,170 --> 00:00:29,470 Speaker 1: recently and saw some news coverage of a clinical trial 7 00:00:29,590 --> 00:00:34,519 Speaker 1: of a vaccine that is meant to help prevent recurrences 8 00:00:34,680 --> 00:00:38,560 Speaker 1: of melanoma in people who have melanoma. And one of 9 00:00:38,580 --> 00:00:41,460 Speaker 1: the things that came up in this news segment was 10 00:00:41,479 --> 00:00:45,770 Speaker 1: a move to describe these kinds of therapies as immunotherapy 11 00:00:45,810 --> 00:00:50,860 Speaker 1: rather than as vaccines. because of the anti-vaccine movements and 12 00:00:51,440 --> 00:00:55,980 Speaker 1: its impacts on things like funding for mRNA research. And 13 00:00:56,040 --> 00:00:58,780 Speaker 1: as I was being frustrated about that, I thought, hey, 14 00:00:58,840 --> 00:01:04,209 Speaker 1: don't you have something about immunotherapy on your shortlist for episodes? 15 00:01:04,390 --> 00:01:08,090 Speaker 1: And I did. Over the course of working on this episode, though, 16 00:01:08,330 --> 00:01:13,490 Speaker 1: it shifted from an overall history of immunotherapy to focus 17 00:01:13,590 --> 00:01:17,530 Speaker 1: on one specific part of that history. And that's the 18 00:01:17,590 --> 00:01:21,940 Speaker 1: work of William B. Coley, who started using a bacterial 19 00:01:22,060 --> 00:01:27,080 Speaker 1: infection to treat cancers in the late 19th century, which 20 00:01:27,140 --> 00:01:31,540 Speaker 1: was one of the earliest uses of an immunotherapy. So 21 00:01:31,560 --> 00:01:33,780 Speaker 1: we're going to start here with a little bit of background. 22 00:01:34,480 --> 00:01:38,380 Speaker 1: Immunotherapy can be defined as anything that modifies the immune 23 00:01:38,420 --> 00:01:43,740 Speaker 1: system in some way, generally activating or suppressing it. Sometimes 24 00:01:43,900 --> 00:01:48,920 Speaker 1: prophylactic vaccines are included under the broad definition of immunotherapy, 25 00:01:49,020 --> 00:01:54,130 Speaker 1: so some histories of immunotherapy start with variolation. That is 26 00:01:54,250 --> 00:01:58,110 Speaker 1: using material from smallpox sores to stimulate the immune system 27 00:01:58,170 --> 00:02:02,310 Speaker 1: to create antibodies, leading to a typically milder case of 28 00:02:02,370 --> 00:02:07,580 Speaker 1: smallpox and lifelong immunity to it. The practice of variolation 29 00:02:07,830 --> 00:02:10,610 Speaker 1: dates back hundreds of years, at least, and it is 30 00:02:10,650 --> 00:02:13,330 Speaker 1: something that we have talked about in our episodes on 31 00:02:13,450 --> 00:02:17,510 Speaker 1: Edward Jenner and the eradication of smallpox. As I was 32 00:02:17,570 --> 00:02:23,250 Speaker 1: researching this, there seemed to be some... not exactly debate, 33 00:02:23,310 --> 00:02:26,270 Speaker 1: but kind of a lack of consistency about whether people 34 00:02:26,389 --> 00:02:31,590 Speaker 1: considered things like the smallpox vaccine, the flu shot, that 35 00:02:31,650 --> 00:02:34,990 Speaker 1: kind of thing to fall under the umbrella of immunotherapy 36 00:02:35,030 --> 00:02:39,630 Speaker 1: or not, or whether it's only the therapeutic vaccines, not 37 00:02:39,690 --> 00:02:44,510 Speaker 1: the more preventive ones that are considered immunotherapy. I can't 38 00:02:44,810 --> 00:02:47,760 Speaker 1: answer that question conclusively. I do not work in that field. 39 00:02:48,520 --> 00:02:53,280 Speaker 1: But today, the term immunotherapy is most often used in 40 00:02:53,300 --> 00:02:58,260 Speaker 1: the context of cancer treatment, activating a person's own immune 41 00:02:58,320 --> 00:03:02,440 Speaker 1: system to recognize and fight cancer cells. One of the 42 00:03:02,490 --> 00:03:07,390 Speaker 1: first attempts to intentionally do this, although it's not necessarily 43 00:03:07,430 --> 00:03:10,750 Speaker 1: what the doctors involved understood that they were doing, started 44 00:03:10,850 --> 00:03:16,050 Speaker 1: in the 19th century. Two different doctors in Germany documented 45 00:03:16,150 --> 00:03:21,770 Speaker 1: patients whose malignant tumors shrank or disappeared completely after they 46 00:03:21,830 --> 00:03:28,150 Speaker 1: contracted a bacterial skin infection known as erysipelas. Sometimes these 47 00:03:28,210 --> 00:03:32,800 Speaker 1: infections were contracted during surgery that attempted to treat the cancers, 48 00:03:33,000 --> 00:03:35,920 Speaker 1: and that was one of the many risks of surgery 49 00:03:36,060 --> 00:03:40,260 Speaker 1: before Joseph Lister developed his antiseptic system for infectious control. 50 00:03:41,100 --> 00:03:45,400 Speaker 1: These doctors were Friedrich Felicin and Wilhelm Busch, and they 51 00:03:45,520 --> 00:03:50,960 Speaker 1: each tried to investigate whether this was a coincidence. In 1868, 52 00:03:50,960 --> 00:03:55,750 Speaker 1: Busch intentionally infected a cancer patient with erysipelas using another 53 00:03:55,830 --> 00:04:01,010 Speaker 1: patient's bedsheets, and he reported that the patient's tumor shrank. 54 00:04:01,790 --> 00:04:06,170 Speaker 1: By 1882, Felicin had identified and isolated the bacteria that 55 00:04:06,270 --> 00:04:11,470 Speaker 1: caused erysipelas. At the time, it was called Streptococcus erysipelas, 56 00:04:11,570 --> 00:04:15,920 Speaker 1: but now it is known as Streptococcus pyogenes. That is 57 00:04:15,980 --> 00:04:19,820 Speaker 1: the same bacterial strain that causes strep throat, scarlet fever, 58 00:04:19,980 --> 00:04:26,050 Speaker 1: and other illnesses and infections. Felicin injected these bacteria directly 59 00:04:26,230 --> 00:04:31,250 Speaker 1: into his patient's tumors. In 1887, German surgeon Paul von 60 00:04:31,290 --> 00:04:35,650 Speaker 1: Bruns also published a paper describing a patient whose tumor 61 00:04:35,750 --> 00:04:41,550 Speaker 1: shrunk after being injected with streptococcus bacteria. William B. Coley 62 00:04:41,589 --> 00:04:44,480 Speaker 1: was not aware of this work when he started working 63 00:04:44,690 --> 00:04:48,440 Speaker 1: as a doctor. He was born in Connecticut on January 12, 1862. 64 00:04:48,440 --> 00:04:52,820 Speaker 1: He went to college at Yale, and then after spending 65 00:04:52,860 --> 00:04:56,000 Speaker 1: some time teaching in Oregon, he went to Harvard Medical School. 66 00:04:56,940 --> 00:05:00,300 Speaker 1: Medical education in the United States was not nearly as 67 00:05:00,460 --> 00:05:04,039 Speaker 1: formalized or extensive as it is today, and he was 68 00:05:04,240 --> 00:05:08,380 Speaker 1: able to enter a three-year medical program as a second-year student, 69 00:05:08,940 --> 00:05:12,700 Speaker 1: thanks to having spent some time accompanying his physician uncle 70 00:05:12,900 --> 00:05:15,719 Speaker 1: on his rounds. I like how it's kind of like 71 00:05:15,880 --> 00:05:18,480 Speaker 1: the way you could get college credit for certain high 72 00:05:18,520 --> 00:05:21,490 Speaker 1: school courses, but it really didn't correlate, except this is 73 00:05:21,550 --> 00:05:24,409 Speaker 1: dealing with people's lives and bodies. Yeah, it doesn't seem 74 00:05:24,450 --> 00:05:27,969 Speaker 1: like he spent all that much time with his uncle, 75 00:05:28,130 --> 00:05:31,089 Speaker 1: but it was considered enough to skip a whole year 76 00:05:31,150 --> 00:05:34,930 Speaker 1: of med school. Coley spent the summer between his two 77 00:05:34,970 --> 00:05:38,490 Speaker 1: years of medical school working as an acting junior surgeon 78 00:05:38,890 --> 00:05:42,120 Speaker 1: at New York Hospital. He had friends who worked there, 79 00:05:42,260 --> 00:05:44,179 Speaker 1: and he was filling in for one of the surgeons 80 00:05:44,339 --> 00:05:48,340 Speaker 1: on staff who was out on leave. Coley started a 81 00:05:48,380 --> 00:05:53,330 Speaker 1: surgical internship at the hospital after graduating from Harvard in 1888, 82 00:05:53,330 --> 00:05:57,330 Speaker 1: and he became a house surgeon there in 1889. Not 83 00:05:57,370 --> 00:06:00,089 Speaker 1: long after that, he was also appointed to the staff 84 00:06:00,230 --> 00:06:03,550 Speaker 1: of the Hospital for the Ruptured and Crippled, later known 85 00:06:03,650 --> 00:06:07,310 Speaker 1: as the Hospital for Special Surgery. That is an orthopedic 86 00:06:07,410 --> 00:06:13,150 Speaker 1: and rheumatologic hospital that still exists today. In 1890, Coley 87 00:06:13,330 --> 00:06:18,270 Speaker 1: treated 17-year-old Elizabeth Daschle, known as Bessie, who had injured 88 00:06:18,330 --> 00:06:20,630 Speaker 1: her hand while on a train trip and was still 89 00:06:20,710 --> 00:06:24,220 Speaker 1: having pain more than a month later. She had seen 90 00:06:24,260 --> 00:06:29,060 Speaker 1: other doctors and tried various treatments and was eventually referred 91 00:06:29,100 --> 00:06:34,320 Speaker 1: to Coley. After some investigation and eventually a biopsy, Coley 92 00:06:34,460 --> 00:06:39,460 Speaker 1: diagnosed her with a periosteal sarcoma, The standard course of 93 00:06:39,550 --> 00:06:42,930 Speaker 1: treatment for this was an amputation, with the hope that 94 00:06:42,950 --> 00:06:46,510 Speaker 1: the cancer had not already spread beyond the amputation site. 95 00:06:47,390 --> 00:06:51,710 Speaker 1: Coley amputated Dashiell's arm below the elbow, but soon there 96 00:06:51,750 --> 00:06:54,950 Speaker 1: were more tumors in other parts of her body. She 97 00:06:54,990 --> 00:06:59,270 Speaker 1: died on January 23, 1891, at the age of 18, 98 00:06:59,270 --> 00:07:04,070 Speaker 1: only about 10 weeks after Coley first examined her. Bessie 99 00:07:04,170 --> 00:07:08,729 Speaker 1: Dashiell's death had a profound effect on William Coley. As 100 00:07:08,770 --> 00:07:11,790 Speaker 1: Tracy said, she was only 18, and she had been 101 00:07:11,850 --> 00:07:15,430 Speaker 1: healthy and active, so the rapid progression of her illness 102 00:07:15,530 --> 00:07:20,190 Speaker 1: and her death seemed particularly shocking and tragic. Coley was 103 00:07:20,230 --> 00:07:23,210 Speaker 1: also only 28 himself, and he was in his first 104 00:07:23,290 --> 00:07:26,680 Speaker 1: year of working as a surgeon. It really bothered him 105 00:07:26,760 --> 00:07:29,780 Speaker 1: that amputation was the only thing that he had been 106 00:07:29,880 --> 00:07:32,740 Speaker 1: able to offer her as a treatment option, and that 107 00:07:32,920 --> 00:07:37,290 Speaker 1: such a life-altering surgery had not even worked. He wanted 108 00:07:37,330 --> 00:07:41,300 Speaker 1: to find some more effective treatments, and he started poring 109 00:07:41,380 --> 00:07:44,700 Speaker 1: over the records at New York Hospital, studying the cases 110 00:07:44,760 --> 00:07:48,660 Speaker 1: of past cancer patients. He went through all the details 111 00:07:48,740 --> 00:07:52,300 Speaker 1: of about 90 cancer patients who had undergone surgery at 112 00:07:52,340 --> 00:07:57,490 Speaker 1: the hospital in the previous 15 years. One record stood out, 113 00:07:57,640 --> 00:08:01,150 Speaker 1: and that was a patient of his colleague, Dr. William T. Bull. 114 00:08:01,950 --> 00:08:05,670 Speaker 1: In Coley's words, quote, among these cases was a small, 115 00:08:05,870 --> 00:08:10,670 Speaker 1: round-celled sarcoma of the neck, four times recurrent. At the 116 00:08:10,770 --> 00:08:14,610 Speaker 1: fifth operation in 1884, Dr. Bull found the tumor to 117 00:08:14,670 --> 00:08:18,170 Speaker 1: involve the deep structures so extensively that it was impossible 118 00:08:18,230 --> 00:08:21,600 Speaker 1: to remove it, and he gave up the attempt. The 119 00:08:21,620 --> 00:08:26,180 Speaker 1: case was regarded as absolutely hopeless when, shortly after the operation, 120 00:08:26,260 --> 00:08:30,320 Speaker 1: the man developed a very severe attack of accidental erysipelas 121 00:08:30,400 --> 00:08:33,569 Speaker 1: in the face and neck, followed two weeks later by 122 00:08:33,610 --> 00:08:36,830 Speaker 1: a second attack. Within a few days after the beginning 123 00:08:36,870 --> 00:08:40,050 Speaker 1: of the first attack, the tumor began to soften and 124 00:08:40,090 --> 00:08:44,270 Speaker 1: decrease rapidly in size. The history stated that when the 125 00:08:44,309 --> 00:08:49,390 Speaker 1: patient left the hospital, his tumors had entirely disappeared. And 126 00:08:49,429 --> 00:08:53,430 Speaker 1: the hospital didn't have any further record of this patient 127 00:08:53,590 --> 00:08:57,530 Speaker 1: after he left, so Coley tracked him down, going door 128 00:08:57,550 --> 00:08:59,930 Speaker 1: to door in the German immigrant community where he was 129 00:09:00,010 --> 00:09:04,490 Speaker 1: likely to have lived. Coley, quote, finally found him alive 130 00:09:04,530 --> 00:09:07,910 Speaker 1: and well, with no evidence of any local or general 131 00:09:07,929 --> 00:09:12,920 Speaker 1: recurrences in the spring of 1891, seven years later. He 132 00:09:12,940 --> 00:09:17,530 Speaker 1: was examined both by Dr. Bull and myself. Coley started 133 00:09:17,580 --> 00:09:21,380 Speaker 1: looking through historical medical literature, and he found other reports 134 00:09:21,440 --> 00:09:25,460 Speaker 1: of patients whose tumors shrank or disappeared after some kind 135 00:09:25,500 --> 00:09:29,580 Speaker 1: of infection. Like Felicin and Bush, Coley decided to see 136 00:09:29,660 --> 00:09:33,860 Speaker 1: if he could replicate this effect. On May 2, 1891, 137 00:09:33,840 --> 00:09:37,280 Speaker 1: he started trying to induce erysipelas in a patient who 138 00:09:37,400 --> 00:09:41,890 Speaker 1: had an inoperable sarcoma of the tonsil and neck. The 139 00:09:41,950 --> 00:09:45,460 Speaker 1: tumors were so large that this patient could not eat 140 00:09:45,540 --> 00:09:49,240 Speaker 1: solid food and could only swallow very small amounts of liquid. 141 00:09:50,080 --> 00:09:53,680 Speaker 1: Coley exposed this patient to bacteria that had been cultured 142 00:09:53,760 --> 00:09:57,010 Speaker 1: in a lab. But for months, he was not able 143 00:09:57,070 --> 00:09:59,730 Speaker 1: to induce a case of erysipelas, no matter how the 144 00:09:59,770 --> 00:10:03,380 Speaker 1: culture were prepared or what method he used to expose 145 00:10:03,420 --> 00:10:07,719 Speaker 1: the patient to them. Finally, in October, he tried a 146 00:10:07,740 --> 00:10:11,480 Speaker 1: culture that a colleague brought him from Robert Koch's laboratory 147 00:10:11,559 --> 00:10:16,679 Speaker 1: in Germany. This injection made the patient very ill, but 148 00:10:16,780 --> 00:10:19,610 Speaker 1: in Coley's words, quote, At the end of two weeks, 149 00:10:19,710 --> 00:10:22,970 Speaker 1: the neck tumor had disappeared and the tonsil tumor had 150 00:10:23,050 --> 00:10:27,410 Speaker 1: decreased in size. The patient remained well for eight years 151 00:10:27,590 --> 00:10:31,729 Speaker 1: and then died in Italy of a local recurrence. We'll 152 00:10:31,770 --> 00:10:35,190 Speaker 1: talk about how Coley started trying to replicate these results 153 00:10:35,429 --> 00:10:48,620 Speaker 1: after a sponsor break. Music In 1892, as his experiments 154 00:10:48,660 --> 00:10:52,510 Speaker 1: with erysipelas were ongoing, William Coley was appointed to the 155 00:10:52,570 --> 00:10:55,650 Speaker 1: staff of New York Cancer Hospital, which was the first 156 00:10:55,730 --> 00:10:59,760 Speaker 1: cancer hospital in the United States. It had opened in 1887. 157 00:10:59,750 --> 00:11:05,610 Speaker 1: It was later renamed Memorial Hospital, and after various moves 158 00:11:05,790 --> 00:11:09,890 Speaker 1: and mergers, it's now known as Memorial Sloan Kettering Cancer Center. 159 00:11:10,980 --> 00:11:13,839 Speaker 1: One of the funders of Coley's work and donor of 160 00:11:13,880 --> 00:11:16,400 Speaker 1: the land where this hospital built a new facility in 161 00:11:16,420 --> 00:11:20,599 Speaker 1: the 1930s was someone else who had been profoundly affected 162 00:11:20,640 --> 00:11:25,160 Speaker 1: by Bessie Daschle's death. That was John D. Rockefeller Jr., 163 00:11:25,130 --> 00:11:28,990 Speaker 1: who had referred to Bessie as his adopted sister. For 164 00:11:29,030 --> 00:11:33,550 Speaker 1: about two years, Coley continued to work with live bacterial cultures. 165 00:11:34,450 --> 00:11:37,920 Speaker 1: His patients were all people whose cancers were considered to 166 00:11:37,960 --> 00:11:41,100 Speaker 1: be incurable, so his this seemed like it could be 167 00:11:41,140 --> 00:11:45,040 Speaker 1: worth the very obvious risks involved. But he continued to 168 00:11:45,080 --> 00:11:49,970 Speaker 1: have difficulty actually inducing an infection. Most of the first 169 00:11:49,970 --> 00:11:53,290 Speaker 1: 10 patients he tried to inoculate with the bacteria did 170 00:11:53,370 --> 00:11:56,710 Speaker 1: not develop erysipelas, but a few did seem to have 171 00:11:57,070 --> 00:12:01,270 Speaker 1: what he described as a slight temporary improvement in their tumors. 172 00:12:02,120 --> 00:12:06,640 Speaker 1: But the two patients who did develop erysipelas had startling results. 173 00:12:07,179 --> 00:12:10,329 Speaker 1: One had an inoperable sarcoma on his back, and that 174 00:12:10,370 --> 00:12:14,650 Speaker 1: had metastasized to his groin. It took weeks for an 175 00:12:14,730 --> 00:12:18,050 Speaker 1: erysipelas infection to take hold, but once it did, in 176 00:12:18,130 --> 00:12:22,150 Speaker 1: Coley's words, the results were, quote, nothing short of marvelous. 177 00:12:22,860 --> 00:12:25,560 Speaker 1: Three weeks from the date of the attack of erysipelas, 178 00:12:25,679 --> 00:12:31,190 Speaker 1: both tumors had entirely disappeared. When this patient's tumor recurred, 179 00:12:31,490 --> 00:12:35,190 Speaker 1: Coley tried the technique again, and the tumor once again disappeared. 180 00:12:36,230 --> 00:12:40,980 Speaker 1: This went on in cycles of recurrence and treatment. Eventually, 181 00:12:41,050 --> 00:12:45,459 Speaker 1: the patient started developing sporadic recurrences of erysipelas, which were 182 00:12:45,540 --> 00:12:49,500 Speaker 1: milder than what Coley had induced and also seemed to 183 00:12:49,580 --> 00:12:52,740 Speaker 1: have a mild effect on the tumors that continued to recur. 184 00:12:53,860 --> 00:12:58,580 Speaker 1: When Coley eventually switched from using live bacteria to using toxins, 185 00:12:58,720 --> 00:13:00,420 Speaker 1: and that's something that we're going to get to in 186 00:13:00,440 --> 00:13:04,290 Speaker 1: just a second, this patient was treated again, and this 187 00:13:04,370 --> 00:13:07,870 Speaker 1: time he remained well for more than three years before 188 00:13:07,910 --> 00:13:12,330 Speaker 1: developing a tumor in his abdomen, which was probably a metastasis. 189 00:13:13,309 --> 00:13:15,960 Speaker 1: The other patient was a woman with a sarcoma in 190 00:13:16,010 --> 00:13:19,480 Speaker 1: her breast, which had already been surgically treated and had 191 00:13:19,540 --> 00:13:24,540 Speaker 1: recurred twice. When Coley treated her, she had three active tumors. 192 00:13:24,960 --> 00:13:27,980 Speaker 1: She developed a case of erysipelas, which Coley described as 193 00:13:28,179 --> 00:13:32,680 Speaker 1: moderately severe after her first treatment, and all three tumors 194 00:13:32,820 --> 00:13:36,550 Speaker 1: decreased in size, with one of them almost completely disappearing. 195 00:13:37,350 --> 00:13:40,710 Speaker 1: But in her case, these tumors never totally went away, 196 00:13:40,929 --> 00:13:44,349 Speaker 1: even after repeated treatment, and she died about six months later. 197 00:13:45,350 --> 00:13:48,189 Speaker 1: All of these first patients had some type of sarcoma, 198 00:13:49,080 --> 00:13:52,700 Speaker 1: Coley was not able to induce an erysipelas infection in 199 00:13:52,920 --> 00:13:55,780 Speaker 1: any of the first carcinoma patients that he tried to treat. 200 00:13:56,559 --> 00:13:59,300 Speaker 1: He also acknowledged how risky this was, which was one 201 00:13:59,320 --> 00:14:01,679 Speaker 1: of the reasons why he was only trying it on 202 00:14:01,740 --> 00:14:06,040 Speaker 1: patients whose cancers were considered inoperable, many of whom had 203 00:14:06,220 --> 00:14:11,689 Speaker 1: already had multiple surgeries and recurrences. He also thought that 204 00:14:11,730 --> 00:14:14,589 Speaker 1: at least a portion of the seeming ability for these 205 00:14:14,670 --> 00:14:18,470 Speaker 1: bacteria to treat cancer came from the toxins that the 206 00:14:18,490 --> 00:14:23,630 Speaker 1: bacteria produced, not from the bacteria on its own. Isolating 207 00:14:23,730 --> 00:14:27,600 Speaker 1: and using the toxins was also potentially less risky than 208 00:14:27,630 --> 00:14:31,820 Speaker 1: trying to intentionally induce a bacterial infection in a patient. 209 00:14:32,380 --> 00:14:34,859 Speaker 1: Two of his early patients after that first group of 210 00:14:34,860 --> 00:14:39,570 Speaker 1: 10 actually died of infection. So in late 1892, he 211 00:14:39,630 --> 00:14:43,910 Speaker 1: started working with bacteriologists to culture the bacteria, kill them 212 00:14:43,960 --> 00:14:48,060 Speaker 1: with heat, and then filter out the toxins. Cooley observed 213 00:14:48,160 --> 00:14:51,140 Speaker 1: that all the tumors that started to shrink went through 214 00:14:51,160 --> 00:14:55,660 Speaker 1: a similar process. Their vascularity decreased, so they started to 215 00:14:55,700 --> 00:14:59,350 Speaker 1: become a lot paler, and they also became more movable 216 00:14:59,530 --> 00:15:03,910 Speaker 1: and less connected to surrounding tissues. They would then soften 217 00:15:04,090 --> 00:15:07,670 Speaker 1: and degrade, and in some cases, they would completely disappear. 218 00:15:08,710 --> 00:15:12,070 Speaker 1: This effect was the same regardless of whether the toxins 219 00:15:12,130 --> 00:15:15,650 Speaker 1: were injected directly into the tumor or elsewhere in the 220 00:15:15,700 --> 00:15:19,560 Speaker 1: patient's body. In words from a paper that he published 221 00:15:19,680 --> 00:15:22,680 Speaker 1: later on, quote, in a certain number of cases, in 222 00:15:22,720 --> 00:15:26,920 Speaker 1: my own experience, a little over 10%, the degenerative process 223 00:15:26,960 --> 00:15:30,440 Speaker 1: has gone on until the complete absorption of the tumors 224 00:15:30,460 --> 00:15:34,220 Speaker 1: has taken place. and the patients have remained cured. In 225 00:15:34,280 --> 00:15:37,850 Speaker 1: other cases, improvement is only temporary, and after a few weeks, 226 00:15:38,130 --> 00:15:41,810 Speaker 1: in spite of continued injections and increased doses, the tumor 227 00:15:41,890 --> 00:15:45,670 Speaker 1: again begins to show signs of growth and continues until 228 00:15:45,710 --> 00:15:49,859 Speaker 1: a fatal issue. In a very few instances, especially in 229 00:15:49,900 --> 00:15:54,200 Speaker 1: cases of very large and vascular tumors, particularly the melanotic type, 230 00:15:54,460 --> 00:15:58,280 Speaker 1: which of late many pathologists are inclined to class as 231 00:15:58,400 --> 00:16:03,300 Speaker 1: carcinoma instead of sarcoma, no marked beneficial effects have been 232 00:16:03,380 --> 00:16:06,870 Speaker 1: noted at any time. In a paper that he published 233 00:16:07,090 --> 00:16:10,950 Speaker 1: in 1909, Coley outlined which patients he had come to 234 00:16:10,990 --> 00:16:14,300 Speaker 1: believe this treatment was suited for. Quote, I would at 235 00:16:14,380 --> 00:16:19,260 Speaker 1: present advocate their use first in all cases of inoperable sarcoma, 236 00:16:19,720 --> 00:16:23,180 Speaker 1: except the melanotic, which are classed as of epithelial origin 237 00:16:23,260 --> 00:16:28,260 Speaker 1: by many pathologists. Second, in cases of sarcoma originating in 238 00:16:28,300 --> 00:16:32,190 Speaker 1: the long bones in which operation means a sacrifice of 239 00:16:32,250 --> 00:16:36,370 Speaker 1: the limb. If in these cases no improvement is noted 240 00:16:36,470 --> 00:16:38,570 Speaker 1: at the end of two to three weeks, I would 241 00:16:38,630 --> 00:16:45,680 Speaker 1: then advise excision, resection, or amputation according to the individual case. Third, 242 00:16:45,840 --> 00:16:49,960 Speaker 1: in all cases of operation for primary sarcoma directly after 243 00:16:50,040 --> 00:16:55,340 Speaker 1: wound healing as a prophylactic against recurrence. Fourth, in addition 244 00:16:55,380 --> 00:16:58,170 Speaker 1: to the foregoing, I think there is a good ground 245 00:16:58,250 --> 00:17:00,770 Speaker 1: for believing that that the use of the mixed toxins 246 00:17:00,890 --> 00:17:05,270 Speaker 1: after all operations for carcinoma would greatly lessen the number 247 00:17:05,390 --> 00:17:11,650 Speaker 1: of recurrences. Coley's belief for why this worked, which I'm 248 00:17:11,670 --> 00:17:13,950 Speaker 1: going to say was not correct, but this is what 249 00:17:13,970 --> 00:17:16,330 Speaker 1: he thought was going on, was that he thought that 250 00:17:16,410 --> 00:17:22,390 Speaker 1: all tumors had a, quote, extrinsic or microbic origin, meaning 251 00:17:22,410 --> 00:17:25,119 Speaker 1: that they were caused by some kind of organism. Uh, 252 00:17:26,690 --> 00:17:30,330 Speaker 1: There are some cancers today that are known to be 253 00:17:30,369 --> 00:17:33,190 Speaker 1: connected to things like specific viruses, but he was sort 254 00:17:33,210 --> 00:17:36,630 Speaker 1: of saying that there is an organism that is causing 255 00:17:36,790 --> 00:17:39,730 Speaker 1: all of these cancers. And he thought that whatever this 256 00:17:39,830 --> 00:17:43,379 Speaker 1: organism was, that humans had a natural immunity to it, 257 00:17:43,460 --> 00:17:46,560 Speaker 1: but that immunity, if it was lowered for some reason, 258 00:17:47,000 --> 00:17:49,760 Speaker 1: meant that the organism could find a site to establish 259 00:17:49,800 --> 00:17:53,949 Speaker 1: itself in the body and start growing a tumor. Injuries 260 00:17:54,250 --> 00:17:57,669 Speaker 1: and mechanical irritation could produce a site in the body 261 00:17:57,830 --> 00:18:01,399 Speaker 1: that was favorable for this organism to establish itself, and 262 00:18:01,580 --> 00:18:05,820 Speaker 1: in his mind, that explained some other research that connected 263 00:18:05,960 --> 00:18:10,980 Speaker 1: some cancers to chronic inflammation or irritation. In his words, quote, 264 00:18:11,119 --> 00:18:15,430 Speaker 1: assuming such extrinsic origin, the action of the toxins appears 265 00:18:15,530 --> 00:18:18,770 Speaker 1: to me to produce certain changes in the blood or serum. 266 00:18:19,290 --> 00:18:23,270 Speaker 1: that restore the weakened or lost immunity or natural resisting 267 00:18:23,350 --> 00:18:26,879 Speaker 1: power of the tissues. And the sarcoma cell, no longer 268 00:18:26,940 --> 00:18:31,340 Speaker 1: finding conditions favorable for further growth and development, undergoes a 269 00:18:31,400 --> 00:18:35,419 Speaker 1: process of degeneration, with absorption in some cases and the 270 00:18:35,460 --> 00:18:39,189 Speaker 1: formation of a slough in others. He also thought the 271 00:18:39,330 --> 00:18:42,970 Speaker 1: fevers that followed exposure to the toxins might also play 272 00:18:43,070 --> 00:18:47,240 Speaker 1: a role. Coley's explanation for why some of his patients 273 00:18:47,300 --> 00:18:51,340 Speaker 1: saw no beneficial effects was that, quote, the tumor cells, 274 00:18:51,440 --> 00:18:54,740 Speaker 1: by reason of great vigor or better nourishment, are more 275 00:18:54,810 --> 00:18:58,810 Speaker 1: resistant and, although receiving a temporary setback by reason of 276 00:18:58,830 --> 00:19:02,909 Speaker 1: the changes in the blood produced by the toxins, soon 277 00:19:03,030 --> 00:19:06,690 Speaker 1: accommodate themselves to the new environment and continue to grow 278 00:19:06,770 --> 00:19:10,550 Speaker 1: as before. Coley presented a paper on this work before 279 00:19:10,590 --> 00:19:16,750 Speaker 1: the American Surgical Association on May 31, 1894. That October, 280 00:19:17,150 --> 00:19:20,460 Speaker 1: an article in the Journal of the American Medical Association 281 00:19:20,560 --> 00:19:25,060 Speaker 1: compared this use of bacterial toxins to the newly developed 282 00:19:25,260 --> 00:19:29,900 Speaker 1: antitoxin treatment for diphtheria. It mentioned the work of Coley, 283 00:19:30,160 --> 00:19:32,460 Speaker 1: as well as that of a Dr. Spronk in Paris 284 00:19:32,680 --> 00:19:36,880 Speaker 1: and Dr. German in Chicago. This report said in part, quote, 285 00:19:36,960 --> 00:19:40,770 Speaker 1: the best method for the utilization of these toxins is 286 00:19:40,850 --> 00:19:45,310 Speaker 1: not as yet positively determined. It is still under experiment, 287 00:19:45,390 --> 00:19:48,590 Speaker 1: and the results thus far demonstrate the necessity of great 288 00:19:48,710 --> 00:19:51,609 Speaker 1: care in the culture of the bacteria and the preparation 289 00:19:51,630 --> 00:19:56,040 Speaker 1: of their toxic products. It ended, quote, let us wait 290 00:19:56,170 --> 00:20:00,640 Speaker 1: patiently the full developments to be made by expert investigations. 291 00:20:01,480 --> 00:20:07,369 Speaker 1: But Coley's work was also unsurprisingly controversial. To some, the 292 00:20:07,470 --> 00:20:12,490 Speaker 1: idea of intentionally exposing patients to a bacterial infection or 293 00:20:12,550 --> 00:20:16,629 Speaker 1: injecting them with toxins seemed antithetical to the practice of medicine. 294 00:20:17,590 --> 00:20:21,129 Speaker 1: Some other doctors who tried to replicate Coley's techniques had 295 00:20:21,210 --> 00:20:25,210 Speaker 1: not been successful. Some of his critics claimed that his 296 00:20:25,250 --> 00:20:30,899 Speaker 1: supposed cures were really just misdiagnoses or coincidences. And it 297 00:20:31,119 --> 00:20:34,369 Speaker 1: just didn't work on some people, which was something that 298 00:20:34,410 --> 00:20:39,360 Speaker 1: Coley acknowledged. On December 15, 1894, so just a few 299 00:20:39,400 --> 00:20:42,480 Speaker 1: months after that October peace, the Journal of the American 300 00:20:42,520 --> 00:20:47,120 Speaker 1: Medical Association published another piece that was called The Failure 301 00:20:47,340 --> 00:20:50,699 Speaker 1: of the Erysipelas Toxins. This read in part, quote, There 302 00:20:50,760 --> 00:20:54,429 Speaker 1: is no longer much question of the entire failure of 303 00:20:54,470 --> 00:20:59,070 Speaker 1: the toxin injections as a cure for sarcomata and malignant growths. 304 00:20:59,710 --> 00:21:02,610 Speaker 1: During the last six months, the alleged remedy has been 305 00:21:02,730 --> 00:21:05,920 Speaker 1: faithfully tried by many surgeons. But so far, not a 306 00:21:05,960 --> 00:21:09,890 Speaker 1: single well-authenticated case of recovery has been reported so far 307 00:21:09,950 --> 00:21:13,609 Speaker 1: as our reading has extended. And the personal experience of 308 00:21:13,710 --> 00:21:17,590 Speaker 1: surgeons of our acquaintance with whom we have conversed demonstrates 309 00:21:17,690 --> 00:21:21,260 Speaker 1: that in all cases in which they tried the erysipelas toxin, 310 00:21:21,380 --> 00:21:26,399 Speaker 1: the result was no improvement. Coley's response was printed in 311 00:21:26,440 --> 00:21:30,469 Speaker 1: the journal in January. He described his surprise at the 312 00:21:30,510 --> 00:21:34,080 Speaker 1: journal's change of views, considering what it had printed in October, 313 00:21:34,580 --> 00:21:36,919 Speaker 1: and he pointed out that he was not just using 314 00:21:36,940 --> 00:21:42,920 Speaker 1: erysipelas toxins, he was also using another bacterium, Bacillus prodigiosus. 315 00:21:43,340 --> 00:21:45,270 Speaker 1: We're going to talk more about that in just a bit. 316 00:21:46,030 --> 00:21:48,429 Speaker 1: He walked through what he had observed in the cases 317 00:21:48,470 --> 00:21:51,810 Speaker 1: that we just discussed and said that, contrary to the 318 00:21:51,850 --> 00:21:55,770 Speaker 1: December 15th article, there were other surgeons that had seen 319 00:21:55,830 --> 00:21:59,810 Speaker 1: positive results. He ended, quote, that a few physicians in 320 00:21:59,850 --> 00:22:03,629 Speaker 1: a very limited number of cases within different preparations of 321 00:22:03,650 --> 00:22:07,290 Speaker 1: the toxins have failed to obtain good results will not, 322 00:22:07,470 --> 00:22:10,139 Speaker 1: I am sure, have great weight in the minds of 323 00:22:10,180 --> 00:22:14,020 Speaker 1: the scientific portion of the profession in determining failure or 324 00:22:14,080 --> 00:22:18,659 Speaker 1: success of this method of treatment of sarcoma. We'll have 325 00:22:18,700 --> 00:22:31,700 Speaker 1: what happened next after a break. Bacillus prodigiosus is known 326 00:22:31,760 --> 00:22:36,030 Speaker 1: today as Serratia marcescens, and it can cause a range 327 00:22:36,070 --> 00:22:39,909 Speaker 1: of infections. Today, those infections most often take place in 328 00:22:39,990 --> 00:22:47,109 Speaker 1: hospitals or long-term care facilities. French physiologist Georges-Henri Roger observed 329 00:22:47,210 --> 00:22:53,080 Speaker 1: that growing Streptococcus erycepolis together with Bacillus prodigiosus produced more 330 00:22:53,300 --> 00:22:56,960 Speaker 1: virulent cultures. William Coley decided to see if he could 331 00:22:57,140 --> 00:23:01,300 Speaker 1: use that trait to make his erycepolis toxins more effective. 332 00:23:02,280 --> 00:23:04,160 Speaker 1: One of the people that he worked with to do 333 00:23:04,220 --> 00:23:08,480 Speaker 1: this was Dr. Martha Tracy, assistant pathologist to the Huntington 334 00:23:08,560 --> 00:23:14,000 Speaker 1: Cancer Research Fund, which was another of Coley's sources of funding. Together, 335 00:23:14,119 --> 00:23:16,050 Speaker 1: the two of them concluded that when it came to 336 00:23:16,090 --> 00:23:19,850 Speaker 1: their impact on tumors, it wasn't just that Bacillus prodigiosus 337 00:23:20,310 --> 00:23:25,950 Speaker 1: had a heightening effect on Streptococcus erysipelas' virulence. Bacillus prodigiosus 338 00:23:25,990 --> 00:23:30,330 Speaker 1: had its own effect on tumors. So Dr. Tracy continued 339 00:23:30,390 --> 00:23:35,200 Speaker 1: to culture them separately, establishing standardized doses for each toxin. 340 00:23:36,250 --> 00:23:38,950 Speaker 1: In addition to her work with Coley, Tracy had a 341 00:23:39,030 --> 00:23:42,310 Speaker 1: huge career of her own, including serving as dean of 342 00:23:42,390 --> 00:23:47,640 Speaker 1: Women's Medical College of Pennsylvania starting in 1917. Coley worked 343 00:23:47,660 --> 00:23:51,480 Speaker 1: with these toxins for about 40 years. Over that time, 344 00:23:51,540 --> 00:23:55,300 Speaker 1: he treated roughly 1,000 cancer patients, and he published about 345 00:23:55,300 --> 00:24:00,230 Speaker 1: 150 papers on his work. And while his results were mixed, 346 00:24:00,630 --> 00:24:04,070 Speaker 1: when the treatment worked, it seemed really incredible. Here's what 347 00:24:04,109 --> 00:24:08,280 Speaker 1: he described in 1909. Quote, I have had 52 cases 348 00:24:08,359 --> 00:24:12,800 Speaker 1: of inoperable sarcoma successfully treated with the mixed toxins of 349 00:24:12,900 --> 00:24:18,600 Speaker 1: erysipelas and bacillus prodigiosus. Of these, 35 have remained well 350 00:24:18,800 --> 00:24:21,040 Speaker 1: from three and a quarter to 16 years, 28 from 351 00:24:21,060 --> 00:24:23,480 Speaker 1: five to 16 years, and 14 from 10 to 16 years. 352 00:24:28,710 --> 00:24:32,689 Speaker 1: To the 36 successful cases published in the American Journal 353 00:24:32,730 --> 00:24:35,510 Speaker 1: of the Medical Sciences in March 1906, I have been 354 00:24:35,570 --> 00:24:40,310 Speaker 1: able to add 16 others. Although Park, Davis, and Company 355 00:24:40,390 --> 00:24:44,300 Speaker 1: produced various preparations of these toxins for medical use starting 356 00:24:45,260 --> 00:24:48,300 Speaker 1: in 1899, they were never the most common treatment for 357 00:24:48,400 --> 00:24:53,310 Speaker 1: inoperable sarcomas for an assortment of reasons. Coley also seems 358 00:24:53,350 --> 00:24:57,210 Speaker 1: to have had a really contentious relationship with James Ewing, 359 00:24:57,570 --> 00:25:00,860 Speaker 1: who was his boss at the cancer hospital, first director 360 00:25:00,940 --> 00:25:04,800 Speaker 1: of the American Association for Cancer Research, and a proponent 361 00:25:04,880 --> 00:25:09,960 Speaker 1: of radiation therapy. Ewing was an opponent of Coley's research. 362 00:25:10,640 --> 00:25:14,290 Speaker 1: Somewhat ironically, many of the cancers Coley was treating would 363 00:25:14,330 --> 00:25:18,670 Speaker 1: later be named Ewing's sarcoma, and Coley also wasn't against 364 00:25:18,750 --> 00:25:22,480 Speaker 1: radiation therapy at all. he was instrumental in getting the 365 00:25:22,540 --> 00:25:26,660 Speaker 1: hospital's first equipment to administer it. Yeah, it really doesn't 366 00:25:26,700 --> 00:25:29,820 Speaker 1: seem like Ewing wanted him working on this bacteria or 367 00:25:29,859 --> 00:25:35,060 Speaker 1: toxin thing at all. Coley's detractors also included the doctors 368 00:25:35,140 --> 00:25:38,639 Speaker 1: who managed the bone sarcoma registry, which was established in 369 00:25:38,660 --> 00:25:42,560 Speaker 1: the 1920s to keep an up-to-date list of living people 370 00:25:42,660 --> 00:25:47,320 Speaker 1: whose bone sarcomas were considered to be cured. Coley had 371 00:25:47,440 --> 00:25:51,240 Speaker 1: difficulty getting his own patients added to this registry, even 372 00:25:51,290 --> 00:25:54,890 Speaker 1: though he was one of the foremost bone cancer surgeons 373 00:25:55,030 --> 00:25:59,360 Speaker 1: in the country. The list's maintainers insisted that his cures 374 00:25:59,930 --> 00:26:04,490 Speaker 1: were really incorrect diagnoses. which seems like a lot of 375 00:26:04,590 --> 00:26:08,260 Speaker 1: times to say that somebody had made an incorrect diagnosis. 376 00:26:08,460 --> 00:26:12,000 Speaker 1: And it probably did not help that he continued to 377 00:26:12,040 --> 00:26:16,080 Speaker 1: believe that all cancers had some kind of microbial origin, 378 00:26:16,740 --> 00:26:21,190 Speaker 1: even after that idea was being disproved. That understandably made 379 00:26:21,230 --> 00:26:25,940 Speaker 1: people question his other conclusions as well. The toxins were 380 00:26:26,040 --> 00:26:30,220 Speaker 1: also difficult to produce and difficult to standardize, and the 381 00:26:30,260 --> 00:26:34,520 Speaker 1: Biologics Control Act of 1902 added an additional layer of 382 00:26:34,600 --> 00:26:38,460 Speaker 1: expense and difficulty. This act gave the Food and Drug 383 00:26:38,510 --> 00:26:43,290 Speaker 1: Administration's Center for Biologics Evaluation and Research the authority to 384 00:26:43,390 --> 00:26:49,670 Speaker 1: regulate biological products, like Coley's toxins, to ensure their safety. Yeah, that, 385 00:26:49,690 --> 00:26:54,270 Speaker 1: of course, added more steps to getting things approved. Aside 386 00:26:54,330 --> 00:26:59,540 Speaker 1: from the innate difficulty in producing standardized versions of these toxins, 387 00:26:59,760 --> 00:27:02,660 Speaker 1: Coley's own methods in using them were kind of all 388 00:27:02,820 --> 00:27:06,620 Speaker 1: over the place. People got different amounts of toxin by 389 00:27:06,740 --> 00:27:10,330 Speaker 1: different methods for different amounts of time. Some of this 390 00:27:10,369 --> 00:27:13,449 Speaker 1: was him trying to figure out what worked and how 391 00:27:13,490 --> 00:27:16,110 Speaker 1: to do it the best, but it also seems like 392 00:27:16,150 --> 00:27:19,550 Speaker 1: some of his treatment decisions were almost made on vibes 393 00:27:19,730 --> 00:27:23,179 Speaker 1: rather than data. He also noted that some of the 394 00:27:23,340 --> 00:27:27,340 Speaker 1: other doctors who used his toxins kept up their patients' 395 00:27:27,460 --> 00:27:30,960 Speaker 1: treatments for much longer than he would have, acknowledging that 396 00:27:31,080 --> 00:27:34,900 Speaker 1: his shorter length of treatment might explain some of his patients' 397 00:27:35,100 --> 00:27:40,040 Speaker 1: own recurrences. It's possible, though, that Coley's toxins would have 398 00:27:40,060 --> 00:27:43,300 Speaker 1: been more widely used if the timing had been different. 399 00:27:44,300 --> 00:27:50,010 Speaker 1: X-rays were discovered in 1895, and radium was discovered in 1898. 400 00:27:50,010 --> 00:27:56,330 Speaker 1: Radiation therapy quickly became the standard treatment for many inoperable cancers. Yeah, 401 00:27:56,450 --> 00:27:59,840 Speaker 1: both of those discoveries were within the early years of 402 00:27:59,890 --> 00:28:04,720 Speaker 1: him doing and writing about this treatment. In 1934, the 403 00:28:04,800 --> 00:28:08,320 Speaker 1: Journal of the American Medical Association published a statement from 404 00:28:08,359 --> 00:28:11,720 Speaker 1: the Council on Pharmacy and Chemistry that was slightly more 405 00:28:11,859 --> 00:28:15,160 Speaker 1: favorable toward Coley's methods than what the journal had published 406 00:28:15,160 --> 00:28:19,169 Speaker 1: 40 years before. It said in part, quote, it appears 407 00:28:19,340 --> 00:28:24,300 Speaker 1: that undoubtedly the combined toxins of erysipelas and prodigiosis may 408 00:28:24,380 --> 00:28:28,359 Speaker 1: sometimes play a significant role in preventing or retarding malignant 409 00:28:28,460 --> 00:28:33,909 Speaker 1: recurrence or metastases. Occasionally, they may play a curative in 410 00:28:34,170 --> 00:28:40,380 Speaker 1: hopelessly inoperable neoplasms. The council has, for these reasons, retained 411 00:28:40,410 --> 00:28:46,090 Speaker 1: erysipelas and prodigiosus toxins, Coley, in new and non-official remedies 412 00:28:46,230 --> 00:28:50,250 Speaker 1: with a view to facilitating further studies with the product. 413 00:28:51,210 --> 00:28:55,000 Speaker 1: By that point, though, Coley had retired. He died on 414 00:28:55,100 --> 00:29:00,320 Speaker 1: April 16, 1936, at the age of 74. Coley's daughter, 415 00:29:00,560 --> 00:29:04,080 Speaker 1: Helen Coley Knotts, started going through his papers and correspondence 416 00:29:04,200 --> 00:29:06,710 Speaker 1: after his death with the intent that she would write 417 00:29:06,750 --> 00:29:10,690 Speaker 1: a biography of him. Soon, she found herself on a 418 00:29:10,750 --> 00:29:13,990 Speaker 1: deep dive of his work. She was not a doctor. 419 00:29:14,170 --> 00:29:17,750 Speaker 1: She had no formal education beyond high school. But she 420 00:29:17,790 --> 00:29:21,090 Speaker 1: went through all of his publications with a fine-toothed comb 421 00:29:21,130 --> 00:29:25,410 Speaker 1: to try to pinpoint the reasons behind his successes and failures. 422 00:29:26,470 --> 00:29:30,380 Speaker 1: In 1953, she partnered with philanthropist Oliver R. Gray Sr. 423 00:29:30,460 --> 00:29:35,040 Speaker 1: to establish the Cancer Research Institute. One of her other 424 00:29:35,100 --> 00:29:39,330 Speaker 1: sources of funding was Nelson Rockefeller, son of John D. 425 00:29:39,390 --> 00:29:43,070 Speaker 1: Rockefeller Jr. Jr. She served as director of the Cancer 426 00:29:43,130 --> 00:29:47,920 Speaker 1: Research Institute until her death in 2001. Her brother Bradley 427 00:29:47,980 --> 00:29:51,520 Speaker 1: was also an advocate of further study of their father's methods, 428 00:29:51,940 --> 00:29:55,340 Speaker 1: and he became chief of bone surgery at Memorial Hospital 429 00:29:55,800 --> 00:30:00,020 Speaker 1: after their father's retirement. The Cancer Research Institute has an 430 00:30:00,060 --> 00:30:03,440 Speaker 1: award named after Coley today. That is an award for 431 00:30:03,520 --> 00:30:09,240 Speaker 1: distinguished research in basic and tumor immunology. The exact reasons 432 00:30:09,380 --> 00:30:12,969 Speaker 1: for the effects of Coley's toxins on some carcinoma are 433 00:30:13,130 --> 00:30:17,270 Speaker 1: not fully understood, and the parts that are somewhat understood, 434 00:30:18,310 --> 00:30:22,020 Speaker 1: I don't understand. They are not within my ability to explain. 435 00:30:22,550 --> 00:30:26,630 Speaker 1: But there is a cancer treatment today that has some 436 00:30:26,730 --> 00:30:32,540 Speaker 1: definite similarities. In 1959, Lloyd J. Old, the Cancer Research 437 00:30:32,640 --> 00:30:36,980 Speaker 1: Institute's founding scientific and medical director, published a paper in 438 00:30:37,000 --> 00:30:41,780 Speaker 1: the journal Nature, along with other authors. This paper described 439 00:30:41,840 --> 00:30:48,400 Speaker 1: how mice injected with Bacillus calmetgaran, or BCG, became resistant 440 00:30:48,480 --> 00:30:54,790 Speaker 1: to implanted tumors. BCG is a tuberculosis vaccine that is 441 00:30:54,850 --> 00:31:00,090 Speaker 1: made from a weakened version of bovine tuberculosis bacteria. This 442 00:31:00,190 --> 00:31:04,110 Speaker 1: work grew from research that stretched back to the 1920s 443 00:31:04,230 --> 00:31:08,750 Speaker 1: when autopsies conducted at Johns Hopkins showed that people with 444 00:31:08,830 --> 00:31:15,050 Speaker 1: tuberculosis had fewer malignancies than people who did not have it. 445 00:31:15,790 --> 00:31:19,920 Speaker 1: In 1975, Old collaborated with Dr. Elizabeth Carswell and others 446 00:31:20,000 --> 00:31:23,800 Speaker 1: to use BCG in conjunction with one of Coley's toxins 447 00:31:23,900 --> 00:31:27,940 Speaker 1: to stimulate the immune system of mice. They were able 448 00:31:28,050 --> 00:31:31,550 Speaker 1: to extract a cytokine from the mice's blood. That's a 449 00:31:31,610 --> 00:31:35,830 Speaker 1: protein that affects how cells interact and communicate. They named 450 00:31:35,870 --> 00:31:40,840 Speaker 1: this cytokine tumor necrosis factor, or TNF. It both causes 451 00:31:40,880 --> 00:31:46,430 Speaker 1: inflammation and kills tumors. Also in the 1970s, Old and 452 00:31:46,490 --> 00:31:51,510 Speaker 1: other researchers tried introducing BCG into the bladders of patients 453 00:31:51,590 --> 00:31:56,280 Speaker 1: with certain bladder cancers, and they found that BCG stimulated 454 00:31:56,340 --> 00:32:00,719 Speaker 1: the immune system to attack the cancer. The FDA approved 455 00:32:00,800 --> 00:32:04,220 Speaker 1: this use of BCG as a superficial bladder cancer treatment 456 00:32:04,320 --> 00:32:08,820 Speaker 1: in 1990, and it is still used today. Old is 457 00:32:08,880 --> 00:32:13,100 Speaker 1: sometimes described as the founder of cancer immunology, although a 458 00:32:13,160 --> 00:32:16,510 Speaker 1: number of people who have written about Coley argue that 459 00:32:16,550 --> 00:32:20,290 Speaker 1: the two of them should share that title. Coley's toxins 460 00:32:20,510 --> 00:32:24,250 Speaker 1: are not approved for use in the U.S. today. Under 461 00:32:24,290 --> 00:32:28,260 Speaker 1: laws passed in 1962 in the wake of the thalidomide disaster, 462 00:32:28,680 --> 00:32:32,180 Speaker 1: the pharmaceutical industry in the U.S. became a lot more regulated. 463 00:32:33,100 --> 00:32:36,240 Speaker 1: Many drugs that were already in widespread use were exempt 464 00:32:36,300 --> 00:32:40,600 Speaker 1: from the law. But in 1963, the FDA classified Coley's 465 00:32:40,650 --> 00:32:44,380 Speaker 1: toxins as an investigational drug. That meant that it would 466 00:32:44,400 --> 00:32:47,520 Speaker 1: need to go through rigorous clinical testing to be approved 467 00:32:47,580 --> 00:32:52,020 Speaker 1: for use in the U.S. In 1965, the American Cancer 468 00:32:52,060 --> 00:32:56,440 Speaker 1: Society added the toxins to its Unproven Methods of Cancer 469 00:32:56,500 --> 00:33:01,480 Speaker 1: Therapy list. The toxins were removed from that list in 1975, 470 00:33:01,480 --> 00:33:04,560 Speaker 1: but the stigma associated with having been on the list continued. 471 00:33:05,140 --> 00:33:08,350 Speaker 1: and the difficulty and expense of producing the toxins and 472 00:33:08,410 --> 00:33:12,750 Speaker 1: putting them through trials led to their being almost entirely abandoned. 473 00:33:13,650 --> 00:33:17,230 Speaker 1: The Cancer Research Institute did fund a phase one trial 474 00:33:17,270 --> 00:33:20,190 Speaker 1: of the toxins in 2007. In the words of a 475 00:33:20,210 --> 00:33:23,670 Speaker 1: blog post about the toxins at the CRI website, quote, 476 00:33:23,750 --> 00:33:28,580 Speaker 1: the toxins were effective at inducing fever and robust surges 477 00:33:28,690 --> 00:33:32,810 Speaker 1: in cytokines. One patient with metastatic bladder cancer had a 478 00:33:32,930 --> 00:33:37,870 Speaker 1: clear clinical response to treatment, experiencing a 50% reduction in 479 00:33:37,930 --> 00:33:42,590 Speaker 1: his cancer that correlated with elevated levels of cytokines. But 480 00:33:42,630 --> 00:33:46,860 Speaker 1: the difficulty of producing the toxins continues to be an 481 00:33:47,020 --> 00:33:50,620 Speaker 1: issue with the idea of doing further studies on this. 482 00:33:50,720 --> 00:33:53,660 Speaker 1: And also at this point, there are just other newer, 483 00:33:53,960 --> 00:34:00,100 Speaker 1: more sophisticated cancer immunotherapy treatments available. than Coley's toxins. It's 484 00:34:00,240 --> 00:34:03,320 Speaker 1: sort of like something that seems like it could have potential, 485 00:34:03,380 --> 00:34:07,440 Speaker 1: but there's also other stuff that is newly developed and 486 00:34:07,620 --> 00:34:12,739 Speaker 1: is potentially more powerful and more specific. Ba-da-da! Do you 487 00:34:13,660 --> 00:34:17,520 Speaker 1: have listener mail? I do have listener mail. This listener 488 00:34:17,560 --> 00:34:23,540 Speaker 1: mail is from Bruce, and Bruce wrote about our Flying 489 00:34:23,620 --> 00:34:27,870 Speaker 1: Gang episode. and the email is titled, Pirates and Our 490 00:34:27,969 --> 00:34:31,670 Speaker 1: Then Teenager. And it says, Greetings, ladies. I was listening 491 00:34:31,710 --> 00:34:34,970 Speaker 1: to the Flying Gang episode, and you briefly mentioned Anne Bonny. 492 00:34:35,270 --> 00:34:38,870 Speaker 1: I'm old enough that my summer camp experiences included making 493 00:34:39,030 --> 00:34:44,190 Speaker 1: physical things like wallets, belts, or bolo neckties. I will 494 00:34:44,210 --> 00:34:48,739 Speaker 1: pause and say, I also am that old. Yeah. So 495 00:34:48,780 --> 00:34:51,350 Speaker 1: the email goes on to say, one of our daughter's 496 00:34:51,390 --> 00:34:55,750 Speaker 1: summer camps involved making short movies. The camps, in her case, 497 00:34:55,810 --> 00:34:58,850 Speaker 1: were hosted on the beautiful Oglethorpe University campus in the 498 00:34:58,910 --> 00:35:03,880 Speaker 1: Atlanta area. The campers, being teens, tended to make mystery 499 00:35:04,020 --> 00:35:07,959 Speaker 1: or horror-adjacent movies. However, one year, our daughter's group made 500 00:35:08,040 --> 00:35:11,799 Speaker 1: a comedy. The premise was that Anne Bonny had been 501 00:35:11,860 --> 00:35:16,320 Speaker 1: found alive and preserved in the Bermuda Triangle. The government 502 00:35:16,420 --> 00:35:19,359 Speaker 1: is trying to rehabilitate her and get her adapted to 503 00:35:19,420 --> 00:35:23,160 Speaker 1: life in the 21st century. At one point, she's enrolling 504 00:35:23,300 --> 00:35:27,140 Speaker 1: in college. Anne muses, I was skeptical at first. I mean, 505 00:35:27,200 --> 00:35:30,000 Speaker 1: what major is there for someone who loots and pillages 506 00:35:30,100 --> 00:35:33,180 Speaker 1: for a living? Then I realized the answer was staring 507 00:35:33,200 --> 00:35:36,420 Speaker 1: me in the face. Anne then enters a classroom that 508 00:35:36,500 --> 00:35:41,080 Speaker 1: is labeled political science. Anne also applies for a job 509 00:35:41,200 --> 00:35:45,259 Speaker 1: at Starbucks because of the mermaid, of course. When asked 510 00:35:45,320 --> 00:35:47,880 Speaker 1: during her interview if she has any questions, she says, 511 00:35:48,020 --> 00:35:53,640 Speaker 1: what's the conversion from dollars to doubloons? Anyway, thanks for 512 00:35:53,680 --> 00:35:56,339 Speaker 1: the great show and triggering a fun memory. Pod Pet 513 00:35:56,390 --> 00:35:59,210 Speaker 1: Tax is our late German shepherd. Scooby helping wake up 514 00:35:59,270 --> 00:36:04,210 Speaker 1: our also then teenager Bruce. I think this play sounds great. 515 00:36:04,989 --> 00:36:08,390 Speaker 1: It's a movie, right? It's a short film? Yes, it's 516 00:36:08,410 --> 00:36:10,570 Speaker 1: a short film. I said play because I am an 517 00:36:10,650 --> 00:36:12,750 Speaker 1: old person, and that's what we would have been doing 518 00:36:12,790 --> 00:36:17,160 Speaker 1: at summer camp. We would not have been filming anything. So, yeah, 519 00:36:17,200 --> 00:36:21,540 Speaker 1: this is delightful. I'm always so charmed by how hilarious 520 00:36:22,360 --> 00:36:26,780 Speaker 1: and sometimes savage children and teens can be in their humor. 521 00:36:26,800 --> 00:36:31,779 Speaker 1: And then we have a picture of the then teenager 522 00:36:31,930 --> 00:36:40,069 Speaker 1: is entirely obscured. By the German shepherd who is supposedly 523 00:36:40,710 --> 00:36:45,910 Speaker 1: helping be an alarm clock. Shepies. So funny. So thank you. 524 00:36:46,210 --> 00:36:48,430 Speaker 1: I also love that they filmed that at Overthorpe. Because 525 00:36:48,469 --> 00:36:50,620 Speaker 1: I'm like, was that when I was working there? Because 526 00:36:50,660 --> 00:36:54,220 Speaker 1: we used to sometimes have crazy summer camp things going 527 00:36:54,420 --> 00:36:57,680 Speaker 1: on on the quad and about campus. And I would 528 00:36:57,700 --> 00:37:00,680 Speaker 1: be like, ah, these kids. Well, I drank my coffee and. 529 00:37:02,100 --> 00:37:04,800 Speaker 1: When I read this the first time through, I thought, 530 00:37:04,840 --> 00:37:08,250 Speaker 1: do kids not make wallets, belts, or bolo neckties at 531 00:37:08,290 --> 00:37:11,910 Speaker 1: summer camp anymore? I have no idea. I think some do. 532 00:37:12,450 --> 00:37:14,750 Speaker 1: I only went to day camp, and we definitely had 533 00:37:15,210 --> 00:37:20,130 Speaker 1: craft projects that would fit in that genre. My question was, 534 00:37:20,510 --> 00:37:21,950 Speaker 1: do you think you have to go to camp to 535 00:37:21,989 --> 00:37:26,000 Speaker 1: do that stuff? No. I just do it at my house. No. Yeah. 536 00:37:26,040 --> 00:37:29,700 Speaker 1: Now I'm thinking of... Childhood of craft making. So thank 537 00:37:29,719 --> 00:37:33,300 Speaker 1: you so much, Bruce, for this email and this delightful 538 00:37:33,360 --> 00:37:37,950 Speaker 1: story of teens being hilarious. If you're a political science 539 00:37:38,010 --> 00:37:41,590 Speaker 1: major and you are feeling upset by these teenagers' short film, 540 00:37:43,210 --> 00:37:48,370 Speaker 1: it was funny, in my opinion. If you would like 541 00:37:48,410 --> 00:37:51,770 Speaker 1: to send us a note, we're at historypodcasts at iheartradio.com. 542 00:37:52,270 --> 00:37:54,330 Speaker 1: If you would like to see the show notes to 543 00:37:54,489 --> 00:37:59,250 Speaker 1: our episode today, including... All these papers printed back in 544 00:37:59,290 --> 00:38:03,660 Speaker 1: the late 19th, early 20th century. That is at MissingHistory.com. Also, 545 00:38:03,700 --> 00:38:06,640 Speaker 1: you can subscribe to our show on the iHeartRadio app 546 00:38:06,719 --> 00:38:14,120 Speaker 1: and anywhere else you like to get your podcasts. Stuff 547 00:38:14,160 --> 00:38:17,000 Speaker 1: You Missed in History Class is a production of iHeartRadio. 548 00:38:17,300 --> 00:38:21,819 Speaker 1: For more podcasts from iHeartRadio, visit the iHeartRadio app, Apple Podcasts, 549 00:38:22,000 --> 00:38:23,950 Speaker 1: or wherever you listen to your favorite shows.