▎Edited by the WuXi AppTec Content Team

“I can see the evil in the world, and I want to do something good for people—I want to take care of them.”

— Dr. Steven A. Rosenberg

This was the very first wish Steven Rosenberg, just 6 or 7 years old at the time, developed after hearing from his parents about how some of his relatives had lost their lives in the wartime massacre. As he grew older, Rosenberg became a surgeon specializing in cancer treatment. After coming into contact with these cancer patients and witnessing the immense suffering they endured, Rosenberg’s compassionate heart was once again stirred—“I want to ease their pain.”

With this strong conviction, Dr. Rosenberg embarked on the journey to find a cure for cancer. Throughout his career, he remained relentlessly focused, pioneering several "firsts" in the field of immunotherapy for humanity, such as The study first demonstrated the potential of T lymphocytes in human cancer therapy, achieved the first successful insertion of exogenous genes into the human body, and for the first time confirmed that chimeric antigen receptor (CAR) T-cell therapy holds promise for treating human B-cell malignancies. Wait a minute—she has made tremendous contributions to advancing this field. In today’s article, the WuXi AppTec content team will draw on publicly available resources to introduce you to this pioneering immunotherapy expert whose heart is filled with compassion and dedication.

▲Dr. Steven A. Rosenberg (Image source: Produced by the WuXi AppTec Content Team)

The remarkable "self-healing" journeys of two cancer patients have paved the way for them to embark on immunotherapy research.

In 1968, the 28-year-old Rosenberg completed his surgical residency and earned a PhD in biophysics from Harvard University. During his surgical training, he profoundly realized that surgically removing the primary tumor alone was far from enough for cancer patients—this relentless disease would inevitably return, ultimately claiming their lives amid the excruciating agony of metastasis. Beyond the scalpel, he understood that more effective "weapons" were urgently needed to combat cancer. With this goal in mind, Rosenberg embarked on an intensive study of cancer biology, determined to uncover a breakthrough that could turn the tide against this devastating illness.

In 1974, after completing his surgical residency, Dr. Rosenberg joined the National Institutes of Health (NIH), where he served as the Chief of the Surgical Division at the U.S. National Cancer Institute (NCI), an institute under the NIH. While working at the NCI, two cancer patients who had experienced "spontaneous remission" caught Dr. Rosenberg's attention. One patient, diagnosed 12 years earlier with metastatic gastric cancer, miraculously saw his cancer completely vanish—despite having undergone surgery alone, without any additional treatment. What exactly could have caused this remarkable phenomenon? Deep down, Dr. Rosenberg sensed he was close to uncovering the answer.

Following this, the experience of another patient helped clarify the vague answer Dr. Rosenberg had been grappling with. The patient had undergone a kidney transplant, but unfortunately, the transplanted kidney carried primary renal cancer. To prevent the immune system from rejecting the foreign organ, the patient had been undergoing immunosuppressive therapy—yet this very treatment inadvertently allowed the invasive cancer cells to begin expanding and multiplying, eventually being detected by doctors. As a result, the patient had no choice but to discontinue the immunosuppressive regimen, leading immediately to rejection of the transplanted kidney. Surprisingly, the metastatic tumor cells also disappeared along with the patient's restored immune function.

These two cases made Dr. Rosenberg realize that the human immune system holds tremendous potential—by triggering the right immune response, even large vascular tumors could potentially be completely eradicated. If we could somehow direct the human immune system at the doctor's command, perhaps one day curing cancer would no longer be an unattainable dream. And so, Dr. Rosenberg resolutely embarked on a journey to explore ways of harnessing the body's immune system to fight cancer.

The first cancer immunotherapy is born.

Dr. Rosenberg’s research initially focused on a cytokine called interleukin-2 (IL-2). This cytokine is produced by lymphocytes and is released when the body encounters microbial infections. It plays a crucial role in activating the immune system, helping immune cells distinguish between "self" and "non-self."

In the initial study, Dr. Rosenberg treated 66 patients with IL-2, but ultimately failed to prevent the death of even a single patient. In 1984, Dr. Rosenberg updated the IL-2 treatment regimen based on pharmacokinetic studies and administered it to his 67th patient. This time, the patient achieved complete remission of metastatic melanoma and went on to survive for more than 30 years afterward! Subsequently, more patients who received Dr. Rosenberg's newly designed IL-2 treatment regimen were found to have achieved partial remission or even sustained complete remission, with many remaining disease-free for up to 25 years after starting treatment.

Dr. Rosenberg was the first to demonstrate that immunotherapy could cure patients with metastatic cancer, paving the way for the development of the first cancer immunotherapy and sparking a new wave of enthusiasm in immunotherapy research. In 1992, the U.S. FDA approved IL-2 as the first immunotherapy for cancer treatment, specifically for metastatic renal cell carcinoma, and in 1998, it again approved IL-2 as a therapy for metastatic melanoma.

Unleashing the potential of immune cell therapy

Dr. Rosenberg wasn’t satisfied with the development of IL-2 therapy, as he knew his discovery had only scratched the surface of the vast treasure trove that is the human immune system. In 1986, Dr. Rosenberg made another groundbreaking finding— he identified specific lymphocytes (known as tumor-infiltrating lymphocytes, or TILs) within the tumor tissue of a patient with advanced melanoma.

Back then, as researchers delved deeper into tumor immunology, they gradually realized that certain lymphocytes could infiltrate tumors to fight cancer cells. Given these cells' natural ability to battle cancer, couldn't we find a way to rejuvenate them, boost their numbers, and enhance their fighting power?

Dr. Rosenberg and his colleagues subsequently turned this vision into reality—they successfully developed a culture method that uses IL-2 to stimulate TILs and promote their proliferation. When they infused these expanded TIL cells back into the patients, the results lived up to their expectations— Out of the 20 melanoma patients who received this cell therapy, 11 achieved remission. Compared to using IL-2 therapy alone, this cell therapy—later known as adoptive cell immunotherapy—further improved patients' remission rates. In 1988, Dr. Rosenberg, as the first author, published an article in the New England Journal of Medicine. NEJM ) published this study.

In 2002, Dr. Rosenberg once again refined his TIL therapy protocol by introducing a lymphodepleting preconditioning regimen prior to infusing lymphocytes back into patients. This approach enables the infused T cells to proliferate within the patient’s body and exhibit robust functional activity. In 2011, Dr. Rosenberg and his team published long-term follow-up results from multiple studies utilizing this innovative new protocol.

The results showed that in each of the three trials adopting the new approach, nearly or more than half of the patients with refractory melanoma achieved remission. Among them, More than 20% of patients achieved complete tumor regression, and 19 patients continued to maintain complete remission after three years. Dr. Rosenberg’s research has, for the first time, directly demonstrated the significant therapeutic potential of T lymphocytes in human cancer immunotherapy. TIL therapy has now been developed to treat patients with metastatic solid cancers and holds promise as the first T-cell therapy approved for the treatment of solid tumors.

Equip immune cells with powerful genetic weaponry

To further optimize the TIL therapy he developed, Dr. Rosenberg also initiated early-stage research on genetically modifying immune cells. He was the first to use retroviruses to genetically modify TIL cells, successfully introducing exogenous genes into human cells for the first time—and in 1990, he published the research findings in the New England Journal of Medicine.

This study demonstrates that using retroviral gene transduction for human gene therapy is both feasible and safe. The technology enables the introduction of modified genes into human immune cells, enhancing their ability to target cancer cells. This breakthrough holds significant implications for engineering immune cells with greater anti-tumor efficacy—and could potentially pave the way for gene therapies aimed at treating other diseases as well.

At the end of the last century, Dr. Rosenberg and his team demonstrated that T cells could be endowed with new antigen specificity by isolating specific T-cell receptors (TCRs). In 2004, Dr. Rosenberg's team launched the first clinical trial of TCR gene therapy, and among the 15 melanoma patients who received treatment, two achieved complete tumor remission. These patients' own T cells were expanded in vitro and engineered to express TCRs that specifically recognize the MART-1 antigen. The study's findings, published in 2006 in the journal *Science*, marked the first demonstration of the potential of genetically modified T-cell therapy (TCR-T cell therapy) in cancer immunotherapy.

Additionally, Dr. Rosenberg has also, for the first time, demonstrated the potential of genetically engineered CAR-T cells in cancer therapy. In 2010, Dr. Rosenberg and his team at Blood A study published in the magazine reported that a patient with advanced follicular lymphoma achieved remission after receiving CAR-T cell therapy designed to target the B-cell antigen CD19.

Just seven years later, the FDA approved Kymriah, the first CAR-T cell therapy, for market release. As of now, nearly 10 CAR-T therapies have received approval from global regulatory authorities, demonstrating remarkable efficacy in treating blood cancers.

Even in their advanced years, they remain actively engaged at the forefront of scientific research.

Dr. Rosenberg has dedicated his entire career to the field of cancer immunotherapy. Now 84 years old, he is a prolific author, having published over 1,200 scientific papers to date—and his accomplishments and accolades are truly countless. This year alone, Dr. Rosenberg also received recognition—considered one of the leading indicators for the Nobel Prize—for his groundbreaking contributions to advancing CAR-T cell therapy in cancer treatment. Poetry Laureate Award (Citation Laureates).

However, Dr. Rosenberg currently has no plans to retire and remains actively engaged in the forefront of scientific research. In his latest work, Dr. Rosenberg has developed a novel approach that leverages patient-specific tumor cell mutations to apply cell therapy to a variety of common solid epithelial cancers.

In addition to his scientific work, Dr. Rosenberg's contributions to the field of immunotherapy also include mentoring hundreds of surgical oncologists and tumor immunotherapists. Under his guidance, these next-generation scientists have gone on to excel at leading cancer centers worldwide, passionately exploring the mysteries of cancer and relentlessly advancing the field—bringing hope and the possibility of "cure" to an ever-growing number of cancer patients. Let us pay profound respect to this scientist who has dedicated his entire life to pioneering in science with unwavering commitment and tireless dedication!