The First Cell

by Azra Raza

  Harvey and Miriam, Omar and Andrew, and all patients facing terminal illnesses go through unspeakable suffering. They bear with unbearable grace whatever comes their way. There is no yardstick to measure their torment, no easier size to fit their grief, no scales to weigh their agony. No amount of analytic objectivity, no fancy subjective descriptions can contain their deep physical and psychological anguish. They may not have won the war on cancer, but dying was not a failure. In the end, there is no consolation, no answer. The science part can have an end in sight, but the human stories continue. Our patients need not be elevated in death, but remembered for what they endured. Lisa Bonchek Adams, who died of breast cancer in the prime of her life, rejected the stereotype, refused to be pitied, expressed the profundity of acceptance in these heartrending lines:

  When I die

  July 13th, 2012

  When I die don’t think you’ve “lost” me.

  I’ll be right there with you, living on in the memories we have made.

  When I die don’t say I “fought a battle.” Or “lost a battle.” Or “succumbed.”

  Don’t make it sound like I didn’t try hard enough, or have the right attitude, or that I simply gave up.

  When I die don’t say I “passed.”

  That sounds like I walked by you in the corridor at school.

  When I die tell the world what happened.

  Plain and simple.

  No euphemisms, no flowery language, no metaphors.

  Instead, remember me and let my words live on.

  Tell stories of something good I did.

  Give my children a kind word. Let them know what they meant to me. That I would have stayed forever if I could.

  Don’t try to comfort my children by telling them I’m an angel watching over them from heaven or that I’m in a better place:

  There is no better place to me than being here with them.

  They have learned about grief and they will learn more.

  That is part of it all.

  When I die someday just tell the truth:

  I lived, I died.

  The end.

  THE STORY OF CAR-T therapy, its overblown reception notwithstanding, is remarkable. Scientific understanding rarely leads to successful, rationally designed treatments in oncology, a notable exception being chronic myeloid leukemia. More commonly, observations of a positive effect lead to a detailed examination of the molecular mechanism of response and not the other way around. The drug luspatercept is a recent example. This class of drugs was initially developed for a different purpose, but when healthy volunteers showed an unexpected improvement in hemoglobin, it was used to treat anemia in MDS patients. The precise mechanism of action is still being investigated but remains unclear. Immune therapies are an exception to this rule, representing an important revolution in medicine.

  Manipulation of the body’s own immune system to target the cancer is at least a century-old concept. A tremendous amount of knowledge generated regarding the intricate functioning of the immune system is only now starting to become translatable. Briefly, this is how it works. The job of T cells, key soldiers in the defensive army of the body, is to constantly inspect normal cells for expression of abnormal protein fragments or antigens on their surface. If detected, T cells latch on to the target antigen with talons and release toxic chemicals to destroy the offender. Cancer cells evolve strategies to deceive T cells by masquerading as normal cells, or expressing too many antigens, which confuse the attacking T cells. Another tactic cancer cells employ to evade the immune system is to turn off the “Eat me” signal on their surface so that cancer cells are perceived by the immune system as friend rather than foe.

  Chimeric antigen receptor T cell, or CAR-T, therapy is a rationally designed, elaborate approach to overcome these cancer tricks. The question scientists asked was whether the body’s own immune cells could be directed to attack the cancer. One way would be to find something unique on the surface of tumor cells, which T cells could latch on to and do their killing. The problem is that despite looking every which way for fifty years, no real unique cancer-associated antigen has been found. The same proteins that cancer cells express are also expressed on normal cells, just in different amounts. In the example of a B cell cancer, like acute lymphoblastic leukemia—ALL—the leukemia cells and normal B cells both express an antigen called CD19.

  In a clever twist, the scientists who developed CAR-T decided to use the CD19 antigen as the target and send T cells armed with newly engineered claws to latch on to the CD19 antigen and kill all cells—normal and leukemic—carrying this marker in one fell swoop. It proved to be a smashing success for children with relapsed and refractory ALL and is now an FDA-approved treatment for this indication. The problem was that the treatment killed all normal B cells along with the leukemia cells. The function of normal B cells is to produce antibodies to fight infection—immunoglobulins. Ordinarily, one cannot live without B cells, but B cell function can be replicated by infusing immunoglobulins. Possibly, replacement therapy might be necessary for the rest of their lives, because CAR-T cells live for a long time and would keep destroying any emerging normal B cells. What this type of replacement therapy will mean in the long run for the patients is, at present, completely unknown.

  CAR-T therapy has not become a universal treatment for all cancers for a host of reasons, the most important being that not all cellular functions are replaceable like the immunoglobulins for B cells. Furthermore, CAR-T therapy comes with its own set of serious and life-threatening toxicities. To start with, before engineered CAR-T cells can be infused into patients, marrow must be emptied to some extent to make room for them. This calls for treatment with very high doses of chemotherapy similar in intensity to the preparative regimen for a stem cell transplant. This step immediately precludes older patients with comorbid conditions from being considered for CAR-T therapy.

  The second problem relates to the antigens expressed by cancer cells coming from different organs. The cancer-specific mutations affect proteins working inside the cell, while CAR-T recognizes only proteins expressed on the outside of the cell surface. Cancer cells express normal antigens on the outside, and these antigens are unique to cells belonging to different tissues or lineages within the same organ. For example, while all B cells express CD19, all myeloid cells (precursors of red blood cells, white blood cells, and platelets) express CD33. If we wanted to treat acute myeloid leukemia (AML) with CAR-T therapy targeting the antigen CD33, then all myeloid cells would be sought and killed by the superefficient engineered T cells. Unfortunately, there is no rescue of myeloid cells possible like there is for the B cells (with immunoglobulin infusions). A novel approach using CD33 CAR-T cells is being developed where all myeloid cells in an AML patient would be destroyed along with the leukemia cells, and then the patient could be transplanted with donor stem cells from which the CD33 antigen has been removed through genetic engineering. This may work; CD33 is not known to have any vital function as of yet. It is possible that donor myeloid cells lacking this antigen can repopulate the recipient marrow and lead to production of normal myeloid cells sans CD33 while AML cells that expressed CD33 will not be able to survive. If successful, a similar approach could be extended to other cancers as well. But once again, this therapy would only be an option for patients who are candidates for a bone marrow transplant, automatically excluding older individuals over seventy years of age.

  Then there is the issue of off-target killing. Researchers describe how CAR-T therapy can backfire in a review article in the Journal of Immunology Research:

  The first fatal adverse event due to off-tumor recognition by a CAR occurred in a patient with colorectal cancer treated with high numbers of T cells expressing a third generation CAR targeting ERBB2/HER2. The patient developed respiratory distress and cardiac arrests shortly after the T cell transfer and died of multisystem organ failure 5 days later. It was postulated that the CAR T cells recognized ERBB2 expressed at low levels in the lu
ng epithelium, leading to pulmonary toxicity and a cascading cytokine storm with a fatal outcome. Predicted on-target off-tumor toxicity with depletion of normal B-cells has been reported in nearly all patients treated with CD19 CAR T cells, and depending on the CAR configuration, B-cell aplasia lasts from months to years.

  Perhaps the most dreaded complications of CAR-T therapy are the tumor lysis and cytokine release syndromes. Because of the extreme competence of CAR-T cell therapy, billions and billions of leukemia cells are destroyed in one swift blow. Tumor lysis syndrome arises when such massive cell death produces an immense amount of debris—choking up the kidneys—along with release of toxic material from the dying cells as they undergo lysis—that is, as they break apart. This constitutes a true medical emergency, as patients can die of multiple organ failure within hours if the syndrome is not recognized and treated early. Cytokine release syndrome is essentially an overstimulation of the immune system, and it can also be fatal. Financial toxicity is also enormous, costing anywhere from half a million dollars to much more, depending upon the level of complications encountered. The company Novartis has a deal where payment is due only upon proof of success a month after therapy.

  CAR-T therapy in a very small subset of cancer patients with lymphoid disease is fantastically successful, albeit causing severe short-term toxicities and many known and unknown lifelong side effects. It is clear that much work lies ahead before this strategy can be scaled up for general use. Yet the hype surrounding CAR-T is such that practically every patient questions me about why they are being deprived of the magic cure. The results are not always magical:

  Despite high-target, cell-specific killing in vitro and encouraging preclinical efficacies in murine tumor models, clinical responses of adoptively transferred T cells expressing α-folate receptor (FR) specific CAR in ovarian cancer were disappointing. No reduction of tumor burden was seen in the 14 patients studied. The absence of efficacy was ascribed to lack of specific trafficking of the T cells to tumor and short persistence of the transferred T cells.

  The CAR-T hype is similar to the attention CRISPR (clustered regularly interspaced short palindromic repeats) is receiving. This laboratory tool, known popularly as molecular scissors, was described in detail just a few short years ago but has already led to the creation of commercial entities trading in hundreds of millions of dollars, institutions fighting nasty patent wars for its use in custom-designing babies to curing every genetic disease and, of course, cancer. Numerous panels debating the ethics of using this technology to alter human embryos have been conducted before any proof-of-principle studies. Several publications finally emerged. First, the news arrived that CRISPR is efficient in cells lacking a functional copy of the protein p53, that famous “guardian of the genome” and a favorite target of cancer research.

  Then came another bit of bad news: when CRISPR was used to cut specific areas of DNA in human cells, it resulted in large segments of DNA being lost—thousands of base pairs away from the cutting site—strongly suggesting that CRISPR can cause mutagenesis and cancer. Why had it taken several years to show something so essential and basic before all the publicity? Why all the mad rush to commercialize before undertaking even the most fundamental science? If it were a matter of technology, then why so much advance promotion? Such are the vagaries of our field. Beautiful science. Not so, the scientists.

  WE FAILED ANDREW. In countless ways. As oncologists, first and foremost, we failed to provide a cure for his extremely malignant, exceedingly painful cancer. We added insult to injury by offering confusing choices—you can take this therapy or not; either way, it makes no difference. He died a tormented death, and his family had to stand by and watch it happen minute by minute. His sister frantically searched for treatment options. From a distance, I did what I could to connect her to whomever she asked to be in touch with. I knew how futile it was, but when she asked me about CAR-T options, I called Jasmine Zain and Steve Rosen because City of Hope had a CAR-T trial for glioblastoma. Steve put me in touch immediately with the principal investigator of the trial and offered his personal help in every way possible. Jasmine was exceptionally kind and considerate toward Kat, answering every e-mail with not just detailed medical answers but doing so with deep empathy and compassion. How fortunate we are to have such amazing colleagues. Andrew was not a candidate for the CAR-T trial because of the shunt. Kat continued e-mailing protocol sponsors, trying on her own to get his blood tested for genetic mutations, maneuvering the absurd legalities of institutional red tape to get a tube of blood sent from one hospital to another, following up on every lead to secure new treatments for her baby brother.

  For most patients with advanced cancers, the end is extremely painful whether the disease is the killer or the treatment. The experimental trials we offer prolong survival by a few months at best, at the cost of incalculable physical and financial toxicities.

  Did Andrew ever ask to be told his chances of survival? Did he and his family even want to know?

  Was honesty a choice?

  Let us, with deep humility, admit that, alas, we failed Andrew Slootsky.

  KAT

  Andrusha. You were the most incredible baby brother I could have ever wished for—I only would have wished for so many more years. But I’m truly lucky to have been your big sister for twenty-three years.

  I can’t possibly have a favorite memory—they will all be my favorite.

  Your laugh will be one of the hardest things to live without. Its evolution over the years. As a baby, you had this old-man laugh, like Santa: “Ho ho ho.” It would keep reinventing itself throughout the years; it always got younger and younger. I would love your laugh so much that I’d tickle you to tears. And you’d warn me that people could die from laughter, and I wouldn’t believe you. But I guess in the most beautiful way, you were right. On your last day in the hospital, the room was full of laugher—mostly you making all of us laugh. That’s why I’m trying my hardest to just keep laughing and smiling these past few days—I keep telling everyone who starts crying that we should laugh instead. It’s what you’d have wanted us to do.

  You were so good at living. You really had it down without any second thoughts. So now everything I do, I’m going to try to do it better, the way you would have. You always believed in what you put your mind to, and that’s why everything you did was so beautiful and effortless. It just came to you so easily because you cared about it so deeply. You wanted to learn to play something from Amélie or Grizzly Bear or Metric on the piano, and you’d do it. You’d make incredible mixtapes. You made hilarious movies with friends just for fun as a kid, then you’d end up making thought-provoking beautiful films for school. You wanted to live in Paris and learn French—you made it all happen. And we were all so proud of you. In your final days, you’d speak French with some of the hospital staff who found out that you were trilingual, and it was so beautiful to hear you speak and connect with everyone so effortlessly.

  I want to share with everyone what outfits you have with you in whatever Berghain heaven you are partying in at the moment: Andrew is wearing his black Dries blazer with the flower patch at the label, Marni white button-down, black jeans, and his new Pradas he got in LA a few months ago. He has his Saint Laurent sunnies, a blue hat that Carol gave him just a few days ago that says DOING THINGS. He wanted to point to it when people asked what he was up to. It was hard to pick a single outfit for Andrew, so I decided he needed to have a spare. So he also has his moss-green wool suit babushka got him a few months ago, with a Junya Watanabe–print button-down tee we got together at Tokio 7.

  Andrush, I hope you are happy with these two outfits. All your clothing is amazing, but I got to pick this time, and these were my favorites.

  I’ll love you forever.

  SEVEN

  HARVEY

  Death Stared Him in the Face, and He Stared Right Back

  The Moving Finger writes; and, having writ, Moves on: nor all your Piety nor Wit Shall lure it back to canc
el half a line, Nor all your Tears wash out a Word of it.

  —OMAR KHAYYAM

  HARVEY DIED ON MAY 19, 2002, AT 3:20 P.M. THE CAUSE OF death was follicular lymphoma / chronic lymphocytic leukemia. Death had already approached him once: at the age of thirty-four, he was diagnosed with his first cancer. After years of living under the shadow of a relapse, when he was over the fear, death loomed again. Harvey faced both his cancers with courage, remaining astonishingly calm and at peace even as he lay dying.

  Harvey became impatient with “holy men” when they appeared to counsel him during his frequent hospitalizations, especially in the last eighteen months, because he drew no consolation from visions of an afterlife. I saw him waver only once.

  In 1996, our daughter, Sheherzad, developed a high fever and a severe asthmatic attack at the age of two and a half. Harvey’s anxiety was palpable. After hours of our taking turns in the emergency room, rocking and carrying her while her little body was connected to the nebulizer, she finally dozed off. Harvey asked me to step outside. In the silence of a hot, still Chicago night, he said in a tormented voice, “If something happens to her, I am going to kill myself. If there is even a remote chance that those fundamentalists are right and there is a life after death, I don’t want the little one to be alone.”