The Mouse

That Was Immune to Cancer

This article is part one
For part two, Click Here

by Jeffrey Dach MD

Medical students spend hours Injecting cancer cells into mice at Wake Forest Medical School in North Carolina. yielding many medical studies and publications over the years.  Left Image: Lab Mice courtesy of wikimedia commons.

Chance Favors the Prepared Mind – Luis Pasteur

Typically, all the mice die of cancer.  However, one day, something unexpected happened.  One mouse did not die.  It lived and flourished.  This was the discovery of the “mouse that could kill cancer.”

Spontaneous Regression of Cancer in the Mouse

Once identified as a “cancer killing” mouse, the little furry fellow was earmarked for study.  These were exciting times in the lab.  Researchers in the lab asked some urgent questions. Why didn’t this mouse get cancer and abdominal fluid (ascites) like all the others?  How was this mouse able to defeat the injected cancer cells? What was the mechanism for the killing the cancer cells?

Immune to Cancer

Over the next 3 years, more studies showed these mice are immune to cancer, a trait innate to this strain of mouse.  Its genetic..The  mouse’s immunity to cancer was genetically determined.  In other words, this strain of mouse has an immune system that fights cancer by sending the immune cells, the macrophages and white cells (leukocytes), to kill the cancer cells, as if they were just another microbial invader. These mice were given the name, SR/CR mice for Spontaneous Regression/Complete Resistant (to Cancer).(2)

Saving All the Other Mice From Cancer

What about the other normal mice? They had no immunity and promptly died of cancer.
Could these normal mice be saved by infusing the macrophages (white cells) from the SR/CR mice ?

More experiments quickly confirmed this was true.  Cancer resistance could be transferred to normal mice transfused with white blood cells (macrophages) from SR/CR mice.(3)  In addition, the protective SR/CR white cells could be stockpiled in cold storage, infused weeks later, and still retain activity.(4)

Human Mice – Spontaneous Regression of Cancer

What about us humans?  Do we have a similar immunity to cancer, with some humans able to resist cancer?  Yes, and this is called spontaneous regression  (remission) of cancer, which has been reported for virtually all cancers many times in the medical literature.  Spontaneous regression can be seen in neuroblastoma, renal cell carcinoma, malignant melanoma and lymphomas/leukemias (see Papac RJ and Chodorowski Z)
(5)(6)

Dr William Osler, a legendary and revered doctor reported 14 cases of breast cancer spontaneous remission.  (The Medical Aspects of Carcinoma of the Breast, with a Note on the Spontaneous Disappearance of Secondary Growths, OSLER W., American Medicine: April 6 1901; 17-19; 63-66.)   I have seen a documented case of spontaneous regression of breast cancer.  A study by Dr Gilbert Welch concluded that small breast cancers may spontaneously regress.  Gina Kolata wrote a New York Times piece about it.

Adoptive Immunotherapy – Dr Steven A Rosenberg NIH

Working from the mouse model in which cancer resistance is transferred by white blood cells called T lymphocytes, further work in humans by Steven A Rosenberg MD PhD shows great promise.  As chief of surgery at the National Cancer Institute, NIH, Dr Rosenberg has developed a cancer treatment using immunotherapy with T cells infused into cancer patients.

His results have been remarkable.(7)  Dr Rosenberg’s treatment uses a cancer patient’s own T lymphocytes which have innate anti-tumor activity, the lymphocytes are activated and cloned in a test tube, and then reinfused into the cancer patient.  This method is currently the most effective treatment for patients with metastatic melanoma producing tumor regression in 50% of patients. See Rosenberg’s case images showing tumor regression (7).  See Figure 2 from his article showing examples of tumor regression in patients receiving  immune cells, lymphocytes (white cells).

What’s in the Future?

Since Adoptive cell transfer is not a drug, and compete with conventional drug treatment (chemotherapy), the pharmaceutical industry might be hostile to the idea.
T Cell Immune therapy is highly personalized treatment, labour-intensive and requires laboratory expertise.  Each lymphocyte preparation is uniquely created for each patient and this makes it difficult to commercialize.   Where to get the anti-tumor T cells?  Blood banks have been providing stem cells for clinical studies, and might also serve as a source for anti-tumour T cells.

This article is part one
For part two, Click Here

Links and References

(1) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC164507/
Proc Natl Acad Sci U S A. 2003 May 27; 100(11): 6682–6687.
Spontaneous regression of advanced cancer: Identification of a unique genetically determined, age-dependent trait in mice. Zheng Cui, Mark C. Willingham, Amy M. Hicks, Martha A. Alexander-Miller et al.

We have established and studied a colony of mice with a unique trait of host resistance to both ascites and solid cancers induced by transplantable cells. One dramatic manifestation of this trait is age-dependent spontaneous regression of advanced cancers. This powerful resistance segregates as a single-locus dominant trait, is independent of tumor burden, and is effective against cell lines from multiple types of cancer. During spontaneous regression or immediately after exposure, cancer cells provoke a massive infiltration of host leukocytes, which form aggregates and rosettes with tumor cells. The cytolytic destruction of cancer cells by innate leukocytes is rapid and specific without apparent damage to normal cells. The mice are healthy and cancer-free and have a normal life span. These observations suggest a previously unrecognized mechanism of immune surveillance, which may have potential for therapy or prevention of cancer.

(2) http://www.cancerimmunity.org/v6p11/060911.htm
Cancer Immunity, Vol. 6, p. 11 (31 October 2006) Submitted: 28 March 2006. Resubmitted: 17 July 2006. Accepted: 28 September 2006. Effector mechanisms of the anti-cancer immune responses of macrophages in SR/CR mice.

Amy M. Hicks et al. The killing of cancer cells in SR/CR mice requires three distinct phases. First, the leukocytes must migrate to the site of cancer cells after sensing their presence. Second, they must recognize the unique properties of the cancer cell surface and make tight contact with it. Third, the effector mechanisms must finally be delivered to target cells. The difference between SR/CR and WT mice seems to lie in one of the first two phases. Upon challenge with cancer cells, WT mice lack leukocyte infiltration and rosette formation. Apparently, the mutation in SR/CR mice renders the leukocytes capable of sensing unique diffusible and surface signals from cancer cells, and of responding to the activation signals by migration and physical contact. Once the first two phases are accomplished, unleashing the pre-existing effector mechanisms for killing seems to ensue by default. Therefore, the mutated gene (or genes) likely determines whether leukocytes interpret the signals from cancer cells as inhibition, as in WT leukocytes, or as activation of migration and target recognition, as in SR/CR leukocytes. Identifying the mutated gene (or genes) will likely explain this unique resistance to cancer through immunity.

(3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458507/?tool=pubmed
Proc Natl Acad Sci U S A. 2006 May 16; 103(20): 7753–7758.  Immunology Transferable anticancer innate immunity in spontaneous regression/complete resistance mice. Amy M. Hicks et al.

(4) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749872/?tool=pubmed
BMC Cancer. 2009; 9: 328. Impact of sex, MHC, and age of recipients on the therapeutic effect of transferred leukocytes from cancer-resistant SR/CR mice
John R Stehle, Jr,1 Michael J Blanks,2 Gregory Riedlinger,1,3 Jung W Kim-Shapiro,1 Anne M Sanders,1 Jonathan M Adams,1 Mark C Willingham,1 and Zheng Cui1
1Department of Pathology, Wake Forest University School of Medicine Winston-Salem, North Carolina 27157, USA

Abstract Background
Spontaneous Regression/Complete Resistant (SR/CR) mice are resistant to cancer through a mechanism that is mediated entirely by leukocytes of innate immunity. Transfer of leukocytes from SR/CR mice can confer cancer resistance in wild-type (WT) recipients in both preventative and therapeutic settings. In the current studies, we investigated factors that may impact the efficacy and functionality of SR/CR donor leukocytes in recipients.

Spontaneous regression of cancer in Humans

(5)http://www.ncbi.nlm.nih.gov/pubmed/9891219
In Vivo. 1998 Nov-Dec;12(6):571-8.
Spontaneous regression of cancer: possible mechanisms. Papac RJ.
Section of Medical Oncology, Yale University School of Medicine, New Haven, CT 06520, USA.

Spontaneous regression of cancer is reported in virtually all types of human cancer, although the greatest number of cases are reported in patients with neuroblastoma, renal cell carcinoma, malignant melanoma and lymhomas/leukemias. Study of patients with these diseases has provided most of the data regarding mechanisms of spontaneous regression. Mechanisms proposed for spontaneous regression of human cancer include: immune mediation, tumor inhibition by growth factors and/or cytokines, induction of differentiation, hormonal mediation, elimination of a carcinogen, tumor necrosis and/or angiogenesis inhibition, psychologic factors, apoptosis and epigenetic mechanisms. Clinical observations and laboratory studies support these concepts to a variable extent. The induction of spontaneous regression may involve multiple mechanisms in some cases although the end result is likely to be either differentiation or cell death. Elucidation of the process of spontaneous regression offers the possibility of improved methods of treating and preventing cancer.

(6) http://www.ncbi.nlm.nih.gov/pubmed/17724923
Przegl Lek. 2007;64(4-5):380-2.
[Spontaneous regression of cancer–review of cases from 1988 to 2006] Chodorowski Z, Anand JS, Wiśniewski M, Madaliński M, Wierzba K, Wiśniewski J.
Katedra i Klinika Chorób Wewnetrznych, Geriatrii i Toksykologii Klinicznej, Akademii Medycznej w Gdańsku.

Spontaneous regression of malignant tumours is a rare and enigmatic phenomenon. We reviewed the cases of spontaneous regression of cancer in medical literature according to MEDLINE database in the period 1988-2006 and compared them with similar reviews from 1900-1987 period. The number of reported cases of spontaneous regression increased steadily in XX century, probably due to a rising interest in this problem and new possibilities of radiological and biopsy examinations. Spontaneous regression of malignancy was reported in almost all types of human cancer, although the greatest number of cases in years 1988-2006 were reported in patients with nephroblastoma, renal cell carcinoma, malignant melanoma, lymphoma. Elucidation of the process of spontaneous regression offers the possibility of improved methods of preventing andlor treating cancer.

Adoptive Cell Therapy ACT

(7) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553205/?tool=pubmed
Nat Rev Cancer. 2008 April; 8(4): 299–308.
Adoptive cell transfer: a clinical path to effective cancer immunotherapy
Steven A. Rosenberg, Nicholas P. Restifo, James C. Yang, Richard A. Morgan, and Mark E. Dudley. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.

Adoptive cell therapy (ACT) using autologous tumour-infiltrating lymphocytes has emerged as the most effective treatment for patients with metastatic melanoma and can mediate objective cancer regression in approximately 50% of patients. The use of donor lymphocytes for ACT is an effective treatment for immunosuppressed patients who develop post-transplant lymphomas. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment.

Figure 2
Examples of objective tumour regressions in patients receiving adoptive cell transfer of autologous anti-tumour lymphocytes following a lymphodepleting preparative regimen
In each case the pretreatment scans and photos are shown on the left and the post-treatment on the right. a | A 45-year-old male with metastatic melanoma to the liver (upper) and right adrenal gland (middle) who was refractory to prior treatment with high dose α interferon as well as high-dose interleukin 2 (IL2). He underwent a rapid regression of metastases and developed vitiligo (lower). b | A 55-year-old male with rapid tumour growth in the axilla as well as multiple brain metastases from metastatic melanoma that was refractory to prior treatment with high dose IL2 who underwent rapid regression of nodal and brain metastases.

The future of ACT

In contrast to common epithelial cancers, melanoma appears to be a tumour that naturally gives rise to anti-tumour T cells. However, other cancers are equally susceptible as the targets of reactive T cells. The susceptibility of melanoma to ACT provides optimism for the application of ACT to common epithelial cancers using TCR gene-modified lymphocytes.

A major problem with the application of ACT is that it is a highly personalized treatment and does not easily fit into current modes of oncological practice. The treatment is labour-intensive and requires laboratory expertise. In essence, a new reagent is created for each patient and this patient-specific nature of the treatment makes it difficult to commercialize. Pharmaceutical and biotechnology companies seek off-the-shelf drugs, easy to produce, vial and administer. From a regulatory standpoint, ACT might be more appropriately delivered as a service rather than as a ‘drug’. Blood banks have been instrumental in providing CD34+ haematopoietic stem cells for clinical studies and might be the ideal location for the generation of the anti-tumour T cells needed for ACT.

As modern science increasingly provides the physician with sophisticated information about the unique aspects of an individual cancer, changes in the modes of care delivery need to accommodate this. The ability to use this patient-specific information can lead to a new era of personalized medicine in which individual treatments, such as ACT, are devised for each patient.Studies of ACT have clearly demonstrated that the administration of highly avid anti-tumour T cells directed against a suitable target can mediate the regression of large, vascularized, metastatic cancers in humans and provide guiding principles as well as encouragement for the further development of immunotherapy for the treatment of patients with cancer.

Jeffrey Dach MD
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